Very low nicotine cigarettes

ABSTRACT

The present disclosure relates to tobacco products, including methodology, devices and compositions, for assisting a smoker to transition from conventional tobacco cigarettes to either e-cigarettes or a tobacco heating device. Provided herein are methodology for switching, along with kits, products and apparatuses.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 17/323,320, filed May 18, 2021, which is acontinuation application of U.S. patent application Ser. No. 17/107,314,filed on Nov. 30, 2020, issued as U.S. Pat. No. 11,017,689 on May 25,2021; which is a continuation application of U.S. patent applicationSer. No. 16/178,298, filed on Nov. 1, 2018, issued as U.S. Pat. No.10,878,717 on Dec. 29, 2020; which is a continuation application of U.S.patent application Ser. No. 16/047,948, filed on Jul. 27, 2018, in theU.S. Patent and Trademark Office, the disclosures of which are hereinincorporated by reference in their entirety.

BACKGROUND 1. Field

The present disclosure relates to tobacco products, including relatedmethodology, devices and compositions.

2. Description of the Related Art

Due to the fact that the tobacco is burned, cigarettes are the mosthazardous tobacco product on the health-risk continuum of tobacco andnicotine products, and medicinal nicotine such as the nicotine patch isthe least hazardous. Tobacco smoke is a complex mixture of more than5,000 smoke constituents which are bound to particles or are free in thegas phase. The temperature of the burning cone at the tip of a cigarettewhile a smoker puffs can reach more than 800° C. The vast majority ofthe more than one billion worldwide tobacco users smoke combustiblecigarettes.

There are essentially two public policy strategies to reduce the harmcaused by smoking. The first strategy is implementation of policies thatencourage smoking cessation. Although cessation yields the greatesthealth benefits, quitting smoking is difficult and a large percentage ofsmokers has no desire to quit. Therefore, in conjunction with policiesencouraging smoking cessation, the second strategy to reduce the harmcaused by smoking is implementing tobacco harm reduction strategies.These include policies that encourage smokers to switch from cigarettesto less hazardous tobacco products. The goal is to migrate as manysmokers of combustible cigarettes as possible to less risky tobacco ornicotine products toward the opposite end of the health-risk continuum.For example, Sweden has among the lowest incidence of smoking in Europe.The use of snus in Sweden has been growing in recent decades whilesmoking incidence has declined partially due to anti-smoking policiessuch as very high cigarette taxes. Switching smokers to snus has notbeen as successful in other countries. Unless used as an adjunct tocigarettes, it is difficult for smokers to exclusively switch to asmokeless tobacco product that is not inhaled such as snus. Althoughcomplete tobacco cessation is the gold standard for reducing the healthrisks of an individual smoker and smoking-related harm at the populationlevel, many public health officials are in favor of tobacco harmreduction policies in conjunction with smoking cessation efforts.

Electronic cigarettes (e-cigarettes) were introduced into the Chinesemarket in 2004 and are generally considered to be less harmful thancombustible cigarettes. E-cigarettes aerosolize a nicotine-containingliquid (e-liquid). Although e-cigarettes have gained popularity,e-cigarettes are a small fraction of worldwide cigarette sales. Eventhough the tobacco industry has invested enormous resources in marketinge-cigarettes, and some in the tobacco control community have publiclysupported e-cigarettes, the adoption rate of e-cigarettes by smokers ofconventional cigarettes has been disappointing and is much lower thanoriginally anticipated by tobacco industry analysts. This low adoptionrate is mainly due to the fact that e-cigarettes are less satisfying tosmokers as compared to conventional cigarettes. Two primary reasons forreduced satisfaction are that nicotine in the vapor of e-cigarettes isnot typically absorbed as well by the lungs and e-cigarettes do notinclude tobacco leaf, reconstituted tobacco or whole extractions oftobacco leaf. The only significant tobacco fraction in the vapor frome-cigarettes is nicotine. Thus, e-cigarettes are generally lesssatisfying to habitual conventional cigarette smokers than they are tonon-smokers. For example, young adults who have never or hardly smokedconventional cigarettes find e-cigarettes more satisfying than doconventional cigarette smokers. E-cigarettes that seem to be the closestto conventional cigarettes in terms of satisfaction are e-cigaretteswhich include e-liquids containing a nicotine salt and an organic acid.

Tobacco smoke contains other active compounds besides nicotine. Forexample, and most importantly, monoamine oxidase (MAO) inhibitors. Thecombination of nicotine and MAO inhibitors in tobacco smoke results inconventional cigarettes being more satisfying to smokers thane-cigarettes or medicinal nicotine products. See, Lanteri et al. 2009,J. Neurosci., Jan. 28; 29(4):987-997 and Hogg 2016, Nicotine Tob Res.May; 18(5):509-23. Moreover, nicotine, MAO inhibitors and other tobaccocompounds are carried on ultra-fine carbon-based particles (<100 nm indiameter) which are easily absorbed by the lungs thereby efficiencydelivering these compounds to the smoker. The virtual instantaneouseffects of inhaling tobacco smoke, including the combination of nicotineand MAO inhibitors, make it difficult for smokers to exclusively switchto e-cigarettes, smokeless tobacco products or medicinal nicotineproducts.

After recognizing the limited potential of e-cigarettes and in an effortto reduce the harm caused by smoking, the tobacco industry has intenselydeveloped heat-not-burn tobacco devices over the last few years. As thename suggests, the tobacco in heat-not-burn tobacco devices is notburned but heated up to approximately 350° C. producing an aerosol forinhalation, which is in contrast to e-cigarettes that aerosolize anicotine-containing liquid (e-liquid). Heat-not-burn tobacco devicesdeliver nicotine and other tobacco compounds similar to that ofconventional cigarettes and have flavors and aromas that are morefamiliar to smokers than e-cigarettes. Examples of heat-not-burn tobaccoproducts, also known as tobacco heating devices, tobacco heatingproducts, and tobacco heating systems, include British AmericanTobacco's Glo®, Philip Morris Product's IQOS® and Japan TobaccoInternational's Ploom®. Smokers of conventional cigarettes generallyrate tobacco heating devices higher than e-cigarettes.

There are dramatically less toxicants in the aerosol produced fromtobacco heating devices compared to smoke produced from combustiblecigarettes. For example, the aerosol in British American Tobacco's Gloproduces around 90 percent less toxicants than smoke from a standard3R4F reference cigarette (approximately 9 mg ‘tar’) in terms of the 9types of harmful components which the World Health Organizationrecommends to reduce (4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone(NNK), N′-nitrosonornicotine (NNN), Acetaldehyde, Acrolein, Benzene,Benzo[a]pyrene, 1,3-Butadiene, Carbon monoxide and Formaldehyde). See,Burns et al. 2008, Tobacco Control, 17:132-141. The aerosol produced bye-cigarettes generally has even less toxicants than the aerosol producedby tobacco heating devices since e-liquids typically contain nicotine,water, flavors, humectants and generally do not contain other tobaccofractions. Due to the significant reduction of most toxicants, if asmoker switches to an e-cigarette or a tobacco heating device, thesmoker's exposure to toxicants is reduced, and it is likely that therisk of tobacco-related disease will also be reduced. Accordingly, a keyin reducing harm at the population level is for a significant number ofsmokers to switch to e-cigarettes or tobacco heating devices. This canbe achieved more rapidly by increasing the adoption rate of e-cigarettesand tobacco heating devices by current cigarette smokers.

SUMMARY

Embodiments of the present disclosure provide tobacco products,including related methodology, devices, and compositions fortransitioning a smoker of cigarettes to an aerosol device.

According to an aspect of an embodiment, there is provided a method oftransitioning a smoker of conventional cigarettes to an aerosol device,the method including: providing the smoker a transition kit including asupply of very low nicotine cigarettes, an aerosol device, andinformation and recommendations for using said cigarettes and aerosoldevice during a transitional period, wherein the supply of very lownicotine cigarettes equals at least 20 percent of the number ofconventional cigarettes the smoker smokes per day multiplied by thenumber of days in the transitional period; wherein the very low nicotinecigarettes contain about equal to or less than 2.0 mg of nicotine percigarette; wherein the transitional period is less than 85 days; andwherein the information and recommendations include the following:instructions for the smoker to stop smoking conventional cigarettes at afirst time point, commencing the transitional period, and after thefirst time point to smoke the very low nicotine cigarettes from thesupply of very low nicotine cigarettes without restriction during thetransitional period; recommendations or instructions that upon thesmoker experiencing an overwhelming craving for a conventionalcigarette, to use the aerosol device without restriction at a secondtime point; recommendations or instructions that after the second timepoint until the end of the transitional period, the smoker may alsosmoke the very low nicotine cigarettes without restriction; andrecommendations or instructions for the smoker to stop smoking the verylow nicotine cigarettes at the end of the transitional period and tocontinue to smoke the aerosol device.

In the method, the aerosol device may include a tobacco heating deviceand a supply of tobacco sticks, wherein the supply of tobacco sticksapproximately equals the number of conventional cigarettes the smokersmokes per day multiplied by the number of days in the transitionalperiod, and wherein each tobacco stick contains at least 2.0 mg ofnicotine per tobacco stick.

In the method, the aerosol device may include e-cigarettes, wherein thee-cigarettes include a rechargeable device and a supply of e-liquidcartridges, wherein the supply of e-liquid cartridges approximatelyequals the product of the number of conventional cigarettes the smokersmokes per day and the number of days in the transitional period,divided by 20, and wherein each e-liquid cartridge contains at least0.10 ml of nicotine by volume.

In the method, the aerosol device may include tobacco heating rods,wherein the supply of tobacco heating rods approximately equals thenumber of conventional cigarettes the smoker smokes per day multipliedby the number of days in the transitional period, and wherein eachtobacco heating rod contains at least 2.0 mg of nicotine.

In the method, the information and recommendations are provided to thesmoker by way of a smartphone, smartwatch or cellular telephone.

According to an aspect of an embodiment, there is provided a method oftransitioning a smoker from dual use of conventional cigarettes and anaerosol device to either using an aerosol device exclusively ormodifying said dual use by reducing the number of cigarettes smoked andincreasing use an aerosol device, the method including: providing thesmoker a transition kit including a supply of very low nicotinecigarettes, an aerosol device, and information and recommendations forusing the very low nicotine cigarettes and an aerosol device during atransitional period, wherein the supply of very low nicotine cigarettesequals at least 20 percent of the number of conventional cigarettes thesmoker smokes per day multiplied by the number of days in thetransitional period; wherein the very low nicotine cigarettes containabout equal to or less than 2.0 mg of nicotine per cigarette; whereinthe transitional period is less than 85 days; wherein the informationand recommendations include the following: instructions for the smokerto stop smoking conventional cigarettes at a first time point,commencing the transitional period, and after the first time point tosmoke the very low nicotine cigarettes from the supply of very lownicotine cigarettes without restriction during the transitional period;recommendations or instructions to also use the aerosol device withoutrestriction after the first time point; and recommendations orinstructions for the smoker to stop smoking the very low nicotinecigarettes at the end of the transitional period and to continue use theaerosol device.

In the method, the aerosol device may include a tobacco heating deviceand a supply of tobacco sticks, wherein the supply of tobacco sticksapproximately equals the number of conventional cigarettes the smokersmokes per day multiplied by the number of days in the transitionalperiod, and wherein each tobacco stick contains at least 2.0 mg ofnicotine per tobacco stick.

In the method, the aerosol device may include e-cigarettes, wherein thee-cigarettes include a rechargeable device and a supply of e-liquidcartridges, wherein the supply of e-liquid cartridges approximatelyequals the product of the number of conventional cigarettes the smokersmokes per day and the number of days in the transitional period,divided by 20, and wherein each e-liquid cartridge contains at least0.10 ml of nicotine by volume.

In the method, the aerosol device may include tobacco heating rods,wherein the supply of tobacco heating rods approximately equals thenumber of conventional cigarettes the smoker smokes per day multipliedby the number of days in the transitional period, and wherein eachtobacco heating rod contains at least 2.0 mg of nicotine.

In the method, the information and recommendations are provided to thesmoker by way of a smartphone, smartwatch or cellular telephone.

According to an aspect of an embodiment, there is provided a very lownicotine cigarette comprising equal to or less than 2.0 mg nicotine percigarette, and more than 0.25 mg anatabine per cigarette.

The very low nicotine cigarette may include at least 0.10 mg anabasineper cigarette.

According to an aspect of an embodiment, there is provided a very lownicotine cigarette comprising equal to or less than 2.0 mg nicotine percigarette and more than 0.10 mg anabasine per cigarette.

According to an aspect of an embodiment, there is provided kit fortransitioning a smoker of conventional cigarettes from smoking saidcigarettes to using an aerosol device during a transitional period ofless than 85 days, said kit comprising one or more compartmentscontaining very low nicotine cigarettes, an aerosol device, andinformation and recommendations, wherein the number of very low nicotinecigarettes is based on a level of consumption of conventional cigarettesby the smoker and a method of transitioning the smoker from smoking saidcigarettes to using said aerosol device employed according to theinformation and recommendations, wherein each of the very low nicotinecigarettes contains equal to or less than 2.0 mg of nicotine percigarette, and wherein the information and recommendations includeinstructions on how the smoker uses the very low nicotine cigarettes andthe aerosol device to transition the smoker from cigarettes to anaerosol device.

In the kit, the aerosol device may include a tobacco heating device anda supply of tobacco sticks, wherein the supply of tobacco sticksapproximately equals the number of conventional cigarettes the smokersmokes per day multiplied by the number of days in the transitionalperiod, and wherein the tobacco sticks contain at least 2.0 mg ofnicotine per tobacco stick.

In the kit, the aerosol device may include e-cigarettes and thee-cigarettes include a rechargeable device and e-liquid cartridges,wherein the supply of e-liquid cartridges approximately equals theproduct of the number of conventional cigarettes the smoker smokes perday and the number of days in the transitional period, divided by 20,and wherein each e-liquid cartridge contains at least 0.10 ml ofnicotine by volume.

In the kit, each of the very low nicotine cigarettes comprises at least1.0 mg of cannabinoids.

In the kit, each of the very low nicotine cigarettes comprises at least2.0 mg of reconstituted cannabis.

According to an aspect of an embodiment, there is provided a cigarettecomprising low nicotine tobacco and very low THCA/THC cannabis buds,wherein the nicotine content of the cigarette is equal to or less than2.0 mg, and wherein the collective THCA and THC content of the cigaretteis equal to or less than 1.25 mg/g.

In the cigarette, the very low THCA/THC cannabis buds are from acannabis plant in which Δ9-tetrahydrocannabinolic acid has been reduced,as compared to a control cannabis plant, by down-regulating theexpression of tetrahydrocannabinolic acid synthase (SEQ ID NO: 21).

According to an aspect of an embodiment, there is provided reconstitutedcannabis made from a cannabis plant in which Δ9-tetrahydrocannabinolicacid has been reduced, as compared to a control cannabis plant, bydown-regulating the expression of tetrahydrocannabinolic acid synthase(SEQ ID NO: 21) in cannabis plants.

According to an aspect of an embodiment, there is provided a very lowcigarette of reconstituted cannabis made from a cannabis plant in whichΔ9-tetrahydrocannabinolic acid has been reduced, as compared to acontrol cannabis plant, by down-regulating the expression oftetrahydrocannabinolic acid synthase (SEQ ID NO: 21) in cannabis plants.

According to an aspect of an embodiment, there is provided an apparatusincluding a communications module; a storage unit storingcomputer-readable instructions; and at least one processor coupled tothe communications module and the storage unit, the at least oneprocessor being configured to execute the computer-readable instructionsto: receive, via the communications unit, a first signal from a deviceof a first smoker, the first signal comprising first demographic datacharacterizing the first smoker and usage data characterizing tobaccouse by the first smoker; in response to receiving the first signal,obtain profile data associated with respective one or more secondsmokers, the profile data comprising (i) second demographic datacharacterizing the respective second smokers and (ii) program dataidentifying a product and method utilized by the respective secondsmokers to transition from conventional cigarettes to an aerosol device;based on an application of a probabilistic algorithm to the firstdemographic data, the usage data, and the profile data, compute a valueindicative of a likelihood that the first smoker transitions from theconventional cigarettes to the an aerosol device using each of aplurality of candidate products and methods for administration to thefirst smoker capable of transitioning the first smoker from theconventional cigarettes to the tobacco an aerosol device from among theprogram data identifying a product and method utilized by the respectivesecond smokers to transition from conventional cigarettes to an aerosoldevice; select one of the candidate products and methods foradministration to the first smoker based on the computed values; andtransmit, via the communications unit, a second signal that identifiesthe selected product and method for administration to the first smokerto the device of the first smoker for the device of the first smoker topresent, in a user interface, information characterizing anadministration of the selected product and service for administration tothe first smoker for transitioning the first smoker from theconventional cigarettes to an aerosol device.

In the apparatus, the storage unit stores a database maintaining theprofile data; and the at least one processor is further configured toobtain, from the database, a portion of the profile data associated withthe one or more second smokers in response to receiving the firstsignal.

In the apparatus, the at least one processor is further configured toidentify the candidate products and methods for administration to thefirst smoker based on the portion of the profile data.

In the apparatus, the probabilistic algorithm comprises at least one ofa statistical process or a machine learning algorithm.

In the apparatus, the first demographic data comprises age or sex; andthe second demographic data comprises age or sex.

In the apparatus, the usage data comprises number of years smoking ornumber of cigarettes per day.

In the apparatus, the at least one processor is further configured toselect the one of the candidate products based on a comparison of thefirst and second demographic data.

In the apparatus, the at least one processor is further configured to:select the one of the candidate products and method for administrationto the first smoker based on a maximum value among the for each of theplurality of candidate products and methods for administration to thefirst smoker capable of transitioning the first smoker from theconventional cigarettes to an aerosol device.

According to an aspect of an embodiment, there is provided a system fortransitioning a smoker from cigarette smoking to an aerosol device, thesystem including: a memory storing a database of smoker profilesrespectively in association with method and product variables oftransition regimens for transitioning smokers from cigarette smoking toan aerosol device, each smoker profile comprising demographic andtobacco use characteristics of the respective smokers; and a processorconfigured to execute a program for a method of providing a recommendedtransition regimen for transitioning a smoker from cigarette smoking toan aerosol device, the method comprising: receiving demographic data ofthe smoker and tobacco usage data of the smoker; determining demographiccharacteristics and tobacco use characteristics of the smoker, based onthe demographic data of the smoker and the tobacco usage data of thesmoker; determining one or more smoker profiles in the database havingdemographic and tobacco use characteristics of the respective smokerssimilar to the demographic characteristics and tobacco usecharacteristics of the smoker; determining method and product variablesof a transition regimen for transitioning the smoker from cigarettesmoking to an aerosol device based on the product variables oftransition regimens for transitioning the smokers from cigarette smokingto an aerosol device; and providing, to the smoker, the transitionregimen for transitioning the smoker from cigarette smoking to anaerosol device.

In the system, the respective smokers comprise smokers successfullytransitioning from cigarette smoking to the tobacco an aerosol device,smokers currently transitioning from cigarette smoking to an aerosoldevice, and smokers unsuccessfully transitioning from cigarette smokingto an aerosol device, and wherein the determining method and productvariables of a transition regimen for transitioning the smoker fromcigarette smoking to an aerosol device comprises: determining, bypredictive learning, method and product variables of a transitionregimen for transitioning the smoker from cigarette smoking to anaerosol device based on weighing the method and product variables oftransition regimens for transitioning the smokers from cigarette smokingto the tobacco an aerosol device according to probabilities that themethod and product variables of transition regimens for transitioningthe smokers from cigarette smoking to an aerosol device will transitionthe smoker from cigarette smoking to an aerosol device.

In the system, each of the demographic of the respective smoker and thedemographic data of the smoker comprises at least one of age, race,gender, ethnicity, national origin, education level, occupation, andmarital status.

In the system, each of the tobacco use characteristics of the smoker andthe tobacco use characteristic of the respective smoker comprises atleast one of number of years smoking, number of packs per day,Fagerstrom dependence score, pack-year rating, total smoke dependencescore, average number of cigarettes smoked per day over the last month,usual cigarette brand, current or previous use of nicotine productsincluding e-cigarettes, current or previous use of a tobacco heatingproduct, current or previous use of any other tobacco products, numberof previous cigarette quit attempts if any, and level of interest inswitching to e-cigarettes or a tobacco heating product compared to levelof interest in quitting tobacco altogether.

In the system, the method and product variables of the transitionregimen the smoker from cigarette smoking to an aerosol device areselected from among the method and product variables of transitionregimens for transitioning smokers from cigarette smoking to an aerosoldevice of the one or more smoker profiles in the database havingdemographic and tobacco use characteristics of the respective smokerssimilar to the demographic characteristics and tobacco usecharacteristics of the smoker.

In the system, the transition regimen for transitioning the smoker fromcigarette smoking to an aerosol device comprises a length of atransitional period, a type of an aerosol device, a type of very lownicotine cigarettes, and recommendations and instructions for using thetype of an aerosol device and the type of the very low nicotinecigarettes during the transitional period.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and/or other aspects of the present disclosure will be moreapparent by describing certain embodiments of the present disclosurewith reference to the accompanying drawings, in which:

FIG. 1 is a diagram illustrating a method of transitioning cigarettesmokers to e-cigarettes or a tobacco heating device;

FIG. 2 is a table of cigarette brand styles showing the weight of thefiller, nicotine content of the filler, and per-cigarette nicotinecontent;

FIG. 3A is a data flow diagram illustrating a system for transitioningcigarette smokers to e-cigarettes or a tobacco heating device;

FIG. 3B is a diagram of an algorithm matching process for identifyingthe optimal method and product variables;

FIG. 4 is a diagram illustrating a method of transitioning cigarettesmokers to e-cigarettes or a tobacco heating device;

FIG. 5 is a table of the levels of minor tobacco alkaloids, includinganatabine and anabasine, in the filler of the fifty top-sellingcigarette brand styles; and

FIG. 6 is a diagram illustrating a clinical trial protocol oftransitioning cigarette smokers to e-cigarettes or a tobacco heatingdevice, according to the method of FIG. 1.

BRIEF DESCRIPTION OF THE SEQUENCES

SEQ ID NO: 1 is a nucleic acid sequence of quinolate phosphoribosyltransferase (QPT). The protein encoded by this nucleic acid sequence isSEQ ID NO: 2.

SEQ ID NO: 3 (Accession No. AF280402.1) is a nucleic acid sequence ofputrescine N-methyltransferase (PMT1). The protein encoded by thisnucleic acid sequence is SEQ ID NO: 4.

SEQ ID NO: 5 (Accession No. AF126809.1) is a nucleic acid sequence ofputrescine N-methyltransferase (PMT2). The protein encoded by thisnucleic acid sequence is SEQ ID NO: 6.

SEQ ID NO: 7 (Accession No. AB289456.1) is a nucleic acid sequence ofN-methylputrescine oxidase (MPO). The protein encoded by this nucleicacid sequence is SEQ ID NO: 8.

SEQ ID NO: 9 (Accession No. AF127242) is a nucleic acid sequence ofOrnithine Decarboxylase (ODC). The protein encoded by this nucleic acidsequence is SEQ ID NO: 10.

SEQ ID NO: 11 is a nucleic acid sequence of NBB1 (BBL gene family). Theprotein encoded by this nucleic acid sequence is SEQ ID NO: 12.

SEQ ID NO: 13 is a nucleic acid sequence of Acyl activating enzyme. Theprotein encoded by this nucleic acid sequence is SEQ ID NO: 14.

SEQ ID NO: 15 (Accession No. AB164375) is a nucleic acid sequence ofOlivetol synthase. The protein encoded by this nucleic acid sequence isSEQ ID NO: 16.

SEQ ID NO: 17 (Accession No. AFN42527.1) is a nucleic acid sequence ofOlivetolic acid cyclase. The protein encoded by this nucleic acidsequence is SEQ ID NO: 18.

SEQ ID NO: 19 is a nucleic acid sequence of Aromatic prenyltransferase.The protein encoded by this nucleic acid sequence is SEQ ID NO: 20.

SEQ ID NO: 21 is a nucleic acid sequence of tetrahydrocannabinolic acidsynthase precursor (Accession No. AB057805.1). The protein encoded bythis nucleic acid sequence is SEQ ID NO: 22.

SEQ ID NO: 23 is a nucleic acid sequence of cannabidiolic acid synthase(Accession No. AB292682). The protein encoded by this nucleic acidsequence is SEQ ID NO: 24.

SEQ ID NO: 25 is a nucleic acid sequence of Cannabichromenic acidsynthase. The protein encoded by this nucleic acid sequence is SEQ IDNO: 26.

DETAILED DESCRIPTION OF THE EMBODIMENTS

E-cigarettes and tobacco heating devices have great potential fortobacco harm reduction; however, important issues need to be rectified.First, after smokers have tried e-cigarettes or tobacco heating devices,the rate of smokers exclusively adopting these aerosol devices is lowand needs to increase. Secondly, of the population of people whoregularly use e-cigarettes or a tobacco heating device, a largepercentage of this population still smoke their usual brand ofconventional cigarettes. This is referred to as “dual use” and as usedherein means that conventional cigarettes are still smoked regularly,either daily or less than daily, in conjunction with e-cigarettes or inconjunction with a tobacco heating device. For example, in PhilipMorris' THS-PBA-07 study in the United States (n=969), Japan (n=638),South Korea (n=843), Italy (n=535), Germany (n=377) and Switzerland(n=416), dual use of cigarettes and IQOS® during the last week of thestudy ranged from 96% in Switzerland to 84% in South Korea. In otherwords, only 4% and 16% of subjects in Switzerland and South Korea,respectively, fell into the “exclusive HeatStick® use” category, whichis defined in the study as ≥95% HeatStick use. These percentages arelower if exclusive use was defined as 99% to 100% HeatStick use.HeatStick is a type of tobacco stick for IQOS® produced and trademarkedby Philip Morris Products S.A.

For e-cigarettes or tobacco heating devices to significantly reduce theharm caused by conventional cigarettes among smokers not interested inquitting tobacco use, it is imperative to exclusively switch as manysmokers as possible from cigarettes to e-cigarettes or tobacco heatingdevices and to do so as quickly as possible. This entails getting asmany smokers as possible to try e-cigarettes or a tobacco heating deviceas quickly as possible and to increase the adoption rate of theseproducts. Among current dual users of conventional cigarettes andtobacco heating products, smoking conventional cigarettes must beeliminated or at least reduced by as much as possible. Among currentdual users of conventional cigarettes and e-cigarettes, smokingconventional cigarettes must be eliminated or at least reduced by asmuch as possible. Recent market data suggests that the rate of smokersswitching to tobacco heating products has leveled off in Japan and othermarkets. The adoption rate at which conventional cigarette smokers, upontrying e-cigarettes or tobacco heating products, switch to theseproducts needs to increase, and among dual users, cigarette use needs tobe entirely replaced with, or at least reduced by, the use ofe-cigarettes or tobacco heating products.

Accordingly, there is an important need for methods and products tofacilitate conventional cigarette smokers who have never triede-cigarettes or a tobacco heating device to switch to using one of thesetypes of products and for dual users of conventional cigarettes ande-cigarettes to exclusively switch to e-cigarettes, and for dual usersof conventional cigarettes and a tobacco heating device to exclusivelyswitch to a tobacco heating device. Embodiments of the presentdisclosure relate to new methods and products to facilitate smokersswitching to e-cigarettes or a tobacco heating device. To facilitatecigarette smokers switching, the conditioning principles of psychologyare utilized during a transitional period wherein the pleasurableeffects of smoke from combustible cigarettes are extinguished while thesmoker is rewarded with aerosol from e-cigarettes or a tobacco heatingdevice.

Smokers of conventional cigarettes immediately experience what is knownas ‘throat impact’ caused by the significant presence of nicotine intobacco smoke. This is the sensation that is immediately felt at theback of the throat by smokers upon inhaling smoke from conventionalcigarettes. The nicotine in the smoke reaches the brain in approximatelyten seconds from the time the smoke is inhaled. This nicotine hit fromsmoking causes mild euphoria. Other effects, which are generallyperceived as positive by smokers, include improvements in concentrationand short-term memory, increased heart rate, and appetite suppression.The cycle of craving a cigarette, smoking a cigarette, obtainingenjoyable rewards during and after smoking the cigarette, and thenstarting the cycle all over again is repeated over and over again bysmokers.

The principles of extinction dictate that when behavior (response),which has been previously reinforced, no longer produces reinforcingconsequences, the behavior eventually stops occurring. The behavior oflighting and smoking conventional nicotine-content combustiblecigarettes is reinforced by throat impact immediately followed by mildeuphoria and the other aforementioned effects. Smoking very low nicotinecigarettes do not result in, to any significant extent, throat impact orother effects of conventional cigarettes. In research studies, smokingvery low nicotine cigarettes reduces daily cigarette use and smokeexposure and results in reduced craving for conventional cigarettes.See, e.g., Donny et al. 2015, N Engl J Med; 373:1340-9. Since very lownicotine cigarettes look, smell and smoke like conventional cigarettes,they are useful for facilitating smokers switching from conventionalcigarettes to e-cigarettes or a tobacco heating device.

Positive reinforcement (reinforcement) occurs when a behavior (response)is rewarding or the behavior is followed by another stimulus that isrewarding, thus increasing the frequency of that behavior. During thetransitional period of the methods disclosed herein, while smoking verylow nicotine cigarettes are extinguishing the pleasurable andreinforcing effects of conventional cigarettes, using e-cigarettes or atobacco heating device reinforces the pleasurable effects of tobacco,thereby facilitating smokers transitioning from conventional cigarettesto either of these less harmful products. For example, as shown in FIG.1, the smoker stops smoking conventional cigarettes to start anexemplary 4-week transitional period 1 of Method A (as further explainedbelow) and starts smoking very low nicotine cigarettes. Upon anoverwhelming craving for a conventional cigarette, the smoker startsusing e-cigarettes or a tobacco heating device and may also continue tosmoke the very low nicotine cigarettes until the end of the transitionalperiod, when at such time the smoker stops smoking very low nicotinecigarettes and continues using e-cigarettes or the tobacco heatingdevice. Unlike e-cigarettes which are popular, approximately 99.95percent of current worldwide smokers has never smoked a very lownicotine cigarette, and approximately 97 percent of current worldwidesmokers has never used a tobacco heating device. Very low nicotinecigarettes, including the improved types disclosed herein, are ideal forsmokers to use in conjunction with the methods disclosed herein totransition smokers to either e-cigarettes or tobacco heating products.In the United States, a very low nicotine cigarette strictly forresearch studies is available and distributed by the National Instituteon Drug Abuse (NIDA) of the National Institutes of Health (NIH) underthe Nicotine Research Cigarettes Drug Supply Program.

Each and every reference cited in this application, including patents,publications of patent applications, non-patent literature, and anyother reference are incorporated herein by reference in their entirety.Each of the terms “about” or “approximately” is used herein to meanroughly, around, nearly, or in the region of. When the term “about” or“approximately” is used in conjunction with a numerical value or range,it modifies that value or range by reasonably extending the boundariesabove and below the numerical values set forth.

As used herein, “cigarette” means any roll of tobacco, which may includenon-tobacco materials, wrapped in paper that when lit combusts andproduces smoke. A cigarette usually also includes a filter, plug wrap(constrains the filtration materials) and tipping paper (holds thecigarette paper to the filter and plug wrap). Glue seals the cigarettepaper together, and if the cigarette has a filter, glue holds theseother components together. The term cigarette shall also include anyroll of tobacco wrapped in any substance containing tobacco (e.g., cigarwrapper) which, because of its appearance, the type of tobacco used inthe filler, or its packaging and labeling, is likely to be offered to,or purchased by, consumers as a cigarette. An example is a ‘littlecigar’ which may include a filter and generally looks very similar to acigarette.

The term cigarettes include roll-your-own cigarettes and make-your-owncigarettes; both types of cigarettes are typically put together by endusers. Roll-your-own cigarettes can simply be made with tobacco andcigarette rolling papers or cigarette rollers can be used to roll thetobacco into the rolling paper. Make-your-own cigarettes are generallymade with a mechanical cigarette injector machine in conjunction withcigarette tubes (e.g., assembled filtered cigarettes without anytobacco). An injector mechanism injects the tobacco into the tobaccotube and the result is a cigarette that looks identical to a typicalpre-rolled commercial cigarette. Cigarettes can also be made by endusers with motorized make-your-own cigarette machines.

As used herein, “filler” means the cumulative smokable material (besidescigarette paper), wrapped in the rod of a cigarette, or in a tobaccostick of a tobacco heating device (or in tobacco heating rod [e.g.,TEEPS®] if no separate holder), selected from the group consisting ofcut tobacco leaf (cut-rag), tobacco stem, reconstituted tobacco,expanded tobacco, cannabis, casings, flavorings and other additiveswhich may include additional alkaloids or cannabinoids from an extrinsicsource. Reconstituted tobacco, also known as recon, is usually includedin the filler of cigarettes and resembles cut-rag tobacco. Expandedtobacco is also usually included in the filler of cigarettes and isprocessed through the expansion of suitable gases so that the tobacco is‘puffed’ resulting in reduced density and greater filling capacity ofthe tobacco rod. Expanded tobacco reduces the weight of tobacco used incigarettes.

As used herein, “reconstituted tobacco sheet” means a tobacco sheetproduced by the rolling or casting of tobacco dust, stems and/orby-products that have been previously finely ground are then mixed witha cohesive agent or binder and may include humectants, flavors,preservatives, cannabinoids and/or additional terpenes. There areessentially two types of reconstituted tobacco in the art, band cast andpaper cast, but for either of these each producer has a slightlydifferent process. Once fabricated, the reconstituted tobacco sheetwhich is essentially ‘recycled’ tobacco, is then cut into small strips.The size and shape of the strips are similar to cut-rag tobacco and this“reconstituted tobacco” may be blended into the filler of cigarettes.See, e.g., U.S. Pat. Nos. 4,270,552 and 5,724,998 and Chapter 11,377-379, Tobacco: Production, Chemistry and Technology, 1999; both ofwhich are incorporated herein by reference in their entireties.

“Alkaloids” are a group of nitrogenous compounds typically of plantorigin. For example, nicotine is the primary alkaloid found incommercialized, conventional cigarette tobacco accounting for, dependingon tobacco type (e.g., flue cured) and variety (e.g., K326), about 95percent of the total alkaloids in tobacco leaf. Anatabine, nornicotine,anabasine and other alkaloids account for the remaining portion of totalalkaloids. Depending on tobacco type and variety, in tobacco leaf,anatabine accounts for about 1% to about 4%, nornicotine accounts forabout 1% to about 3%, and anabasine accounts for about 0.02% to about0.4%. As used herein ‘nicotine,’ ‘anatabine’ and ‘anabasine’ may bederived from any plant species including any species of the genusNicotiana, and any of these alkaloids may also be synthesized, or be ananalog, or be made in the form of salts of organic acids. Syntheticnicotine, synthetic anatabine and synthetic anabasine, analogs ofnicotine, analogs of anatabine and analogs of anabasine, and nicotinesalts of organic acids, anatabine salts of organic acids and anabasinesalts of organic acids, are included in the meaning of nicotine,anatabine and anabasine, respectively. See, e.g., Sisson et al. 1990,Beitrage zur Tabakforschung International, Volume 14, No. 6, June-July.

As used herein, “conventional cigarette” means a cigarette having aconventional nicotine content of at least 9 mg per cigarette.Per-cigarette nicotine content is the product of the weight of thefiller in a cigarette rod and the nicotine content of the filler in thecigarette rod. Popular brands generally contain approximately 13 mgnicotine per cigarette. For example, as shown in FIG. 2, a Marlboro®cigarette (code 102) contains 13.04 mg nicotine, which equals the weightof the filler, 660 mg, multiplied by the nicotine content of the filler,19.75 mg/g. Across the 23 American commercial cigarette brand stylesanalyzed in FIG. 2, per-cigarette nicotine content ranged from 9.94 mg(GPC®—code 116) to 16.18 mg (Parliament®—code 106) and averaged 13.25mg. See, Morton et al. 2008, Regul Toxicol Pharmacol. doi:10.1016/j.yrtph.2008.03.001. However, per-cigarette nicotine content canbe more than 20 mg; these higher nicotine brands are not shown in FIG.2.

The weight of the filler in commercial cigarettes can vary widely acrossbrands and depends on various factors such as the ratio of thecomponents contained in the filler (e.g., whole leaf tobacco is heavierthan expanded tobacco), tobacco rod length and circumference (volume),moisture levels, and the filler density level each cigarette is packed.Across the 23 brand styles analyzed and shown in in FIG. 2, theper-cigarette weight of the filler ranged from 480 mg (Merit®—code 120)to 800 mg (Parliament®—code 106), and the average was 659 mg.

The nicotine content of the filler in commercial cigarettes can alsovary widely across brands. One major factor is the type of tobacco usedand the percentage of each type used. Generally, burley tobacco has thehighest nicotine content followed by flue-cured tobacco and orientaltobacco. Some cigarette brands include flue-cured tobacco without anyburley or oriental, others include flue-cured and burley withoutoriental, and others include all three tobacco types. Most cigarettebrands also contain reconstituted tobacco and expanded tobacco. Anothermajor factor of nicotine content of filler is the amount of non-nicotinecomponents in the filler such as casing and top flavors. Across the 23brand styles analyzed in FIG. 2, the nicotine content of the fillerranged from 16.85 mg/g (GPC—code 116) to 24.27 mg/g (Merit—code 120),the average nicotine content of the filler was 20.18 mg/g, and theaverage nicotine content per cigarette was 13.25 mg.

The 3R4F reference cigarette is supplied to tobacco manufacturers by theKentucky Tobacco Research & Development Center of the University ofKentucky and is a long-established standard for measuring cigarettefiller and smoke chemistry. The tobacco weight (13% OV) of the filler inthe 3R4F reference cigarette is 0.783 gram and the filler contains 20.5mg/g (2.05%) total alkaloids. The cigarette therefore contains about16.05 mg of total alkaloids. Although the nicotine portion of totalalkaloids was not disclosed by the University of Kentucky analysis ofthe 3R4F reference cigarette, since nicotine typically comprisesapproximately 95% of total alkaloids in tobacco, the nicotine content ofthe 3R4F reference cigarette is about 15.7 mg.

As used herein, “very low nicotine cigarette” means a cigarettecontaining 2.0 milligrams (mg) nicotine per cigarette or less such asless than 0.05 mg, 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.30 mg, 0.35 mg,0.40 mg, 0.45 mg, 0.50 mg, 0.55 mg, 0.60 mg, 0.65 mg, 0.70 mg, 0.75 mg,0.80 mg, 0.85 mg, 0.90 mg, 0.95 mg, 1.00 mg, 1.05 mg, 1.10 mg, 1.15 mg,1.20 mg, 1.25 mg, 1.30 mg, 1.35 mg, 1.40 mg, 1.45 mg, 1.50 mg, 1.55 mg,1.60 mg, 1.65 mg, 1.70 mg, 1.75 mg, 1.80 mg 1.85 mg, 1.90 mg or 1.95 mgnicotine per cigarette. This is calculated by multiplying the weight ofthe filler in a cigarette rod by the nicotine content of the filler inthe cigarette rod. For example, a cigarette containing 2.0 mg nicotineand weighing 0.667 gram has filler with a nicotine content of about 3mg/g. Filler having a nicotine content of 3 mg/g equates to anapproximate 85% reduction of the average nicotine content of tobaccofiller of the cigarette brand styles in FIG. 2.

Total alkaloid levels or individual alkaloid levels such as the level ofnicotine, anatabine or anabasine can be measured by several methodsknown in the art. Examples include quantification based on gaschromatography (GC) and high performance liquid chromatography. See,e.g., Lisko et al. 2013, Anal Chem. March 19; 85(6): 3380-3384, whichprovides the following methods used to measure quantities of alkaloidsin the filler of cigarette brands and in tobacco types (e.g., burleytobacco). The analysis of minor alkaloids has been performed with gaschromatography (GC) coupled with a wide spectrum of detection techniquesincluding flame ionization detection (HD), nitrogen-phosphorus detection(NPD), and mass spectrometry (MS). Other analysis approaches haveincluded high-performance liquid chromatography-ultraviolet detection(HPLC-UV), capillary zone electrophoresis-ultraviolet detection(CZE-UV), micellar electrokinetic capillary chromatography-ultravioletdetection (MECC-UV), nitrogen chemiluminescence detection (NCD), andmicroemulsion electrokinetic chromatography-ultraviolet detection(MEEKC-UV). Utilization of gas chromatography-tandem mass spectrometry(GC-MS/MS) in multiple reaction mode (MRM) mode allows for greatercompound specificity by eliminating matrix ions arising from othercompounds that share the same parent mass but lack the correcttransition ion, drastically decreasing background interferences andreducing detection limits. Unless specified insinuated otherwise,analyte measurements (e.g., nicotine) are on a dry weight basis.

As used herein, a “tobacco heating device” is a device that heats, butdoes not burn, tobacco and produces an aerosol, not tobacco smoke. Atobacco heating device may be comprised of a holder, tobacco sticks anda charger. In this exemplary configuration, the IQOS® tobacco stick(HeatStick®), for example, is inserted into the IQOS® holder which heatsthe tobacco material by means of an electronically-controlled heatingblade. The HeatStick® differs from a cigarette in many ways. Forexample, the tobacco in the HeatSticks® for the IQOS® product is madefrom tobacco powder and the tobacco is uniquely processed andspecifically designed to function with the holder to produce an aerosol.Unlike a cigarette that contains tobacco cut-filler (tobacco leaf cut insmall pieces found in cigarettes), the HeatStick® contains speciallyprocessed tobacco that has been reconstituted into sheets (termedcast-leaf) following the addition of water, glycerin, guar gum(hemi-cellulose), and cellulose fibers. This tobacco stick, unlike acigarette, contains two unique and independent filters, a polymer-filmfilter to cool the aerosol and a low-density cellulose acetatemouthpiece filter to mimic this aspect of a cigarette. A hollow acetatetube separates the tobacco plug and the polymer-film filter. The chargerrecharges the holder and stores enough energy for the use of around 20tobacco sticks and can be recharged from household power.

IQOS® is operated by the user inserting a tobacco stick into the holderand turning on the device by means of a switch. These steps initiate theheating of the tobacco via the heating blade inserted into the tobaccoplug. The heating, which is electronically controlled, combined with theuniquely processed tobacco, prevent combustion from occurring. Theholder supplies heat to the tobacco stick through the heating blade forabout six minutes and allows up to 14 puffs to be drawn by the userduring that time. The temperature of the heating blade is carefullycontrolled and the energy supply to the blade is cut if its operatingtemperature exceeds 350° C. The temperature measured in the tobacconever attains 350° C., and most of the tobacco remains below 250° C.

IQOS® produces an aerosol that has a very different composition thancigarette smoke due to heating tobacco below the level of combustion.The aerosol contains significantly reduced levels of harmful andpotentially harmful constituents (HPHCs), as compared with cigarettesmoke, and is composed mainly of water, glycerin and nicotine. Thechemical analysis of the aerosol generated by IQOS® confirmed that IQOS®aerosol contains substantially reduced levels of HPHCs. On average, thisequates to >90% reduction in the levels of HPHCs compared with smokefrom the 3R4F reference cigarette.

In another exemplary configuration, a tobacco heating device is ignitedlike a conventional cigarette. There may not be any holder, charger orbattery and the tobacco may be directly heated in a tobacco heating rod.For example, an ignited carbon heat source heats (and does not burn) thetobacco and produces an aerosol similar to tobacco heating devices whichcomprise of separate tobacco sticks. The types of tobacco heatingdevices with carbon heat sources, for example, closely resemble atypical cigarette physically, but do not burn. The disposable heatingelement is contained in each rod producing the aerosol that is inhaled,known herein as a “tobacco heating rod” or “heating rod.” These types oftobacco heating devices also have significantly reduced levels of HPHCs.An example is TEEPS® which is being developed by Philip MorrisInternational. Other examples include Eclipse® and Revo®, which werepreviously sold in the United States but are no longer on the market. Inanother exemplary configuration, a tobacco heating device has no holderor charger and includes a battery in every heating rod and each heatingrod may be disposable. Accordingly, it is understood that any devicethat heats tobacco (or tobacco extract or a form of tobacco such asreconstituted tobacco) below combustion (and does not burn tobacco) toproduce an aerosol is a tobacco heating device (or any other synonymousterm), regardless whether there are separate tobacco sticks from theholder or heating element, whether charging a battery is required or abattery is even required, whether something needs to be ignited such asthe end of a carbon heat source, and/or whether any electronics areinvolved. Tobacco heating device, tobacco heating product, heat-not-burntobacco device, and heat-not-burn tobacco product as used herein aresynonymous.

A tobacco stick or heating rod contains less tobacco compared with acigarette. For example, each HeatStick® contains about 320 mg comparedto about 480 to about 900 mg of filler in conventional cigarettes. Thenicotine content of a HeatStick® is about 4.8 mg which is much less thana conventional cigarette even though IQOS® delivers nicotine to thesmoker at comparable levels as conventional cigarettes. Less tobacco isrequired in a tobacco stick or heating rod since there is no combustionincluding between puffs. See, Farsalinos et al. 2017, Nicotine Tob Res.June 16. doi: 10.1093/ntr/ntx138; Tobacco Heating System (IQOS),Briefing Document, December 2017, Prepared by Philip Morris ProductsS.A. for the Jan. 24-25, 2018 Tobacco Products Scientific AdvisoryCommittee Meeting. Each tobacco stick for a tobacco heating device andeach tobacco heating rod which produces aerosol without a separateholder (the element produces the heat in the rod itself) may contain atleast the following nicotine contents: 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg,1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg,2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg,3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg,4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg,5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg,5.9 mg, 6.0 mg 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg,6.8 mg, 6.9 mg, 7.0 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg,7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg,8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg or 9.0 mg.

As used herein, an “aerosol device” means any device that produces anaerosol for inhalation such as any e-cigarette or tobacco heatingdevice.

Typical components of e-cigarettes include a rechargeable device whichincludes a heating coil and atomizer that transforms the e-liquid to anaerosol, cartridge or the like (sticks or pods) contains the e-liquid,mouthpiece and battery in the rechargeable device. Although there aremany appearances and designs that may encompass varying steps, theygenerally operate by drawing on the e-cigarette, activating a heatingelement which aerosolizes the e-liquid, and inhaling the liquid aerosol.E-liquids typically contain nicotine, water, flavors and humectants. Thehumectant acts as a carrier solvent which dissolves the nicotine andflavors and aerosolizes at a certain temperature on the atomizer of thee-cigarette. Typically, propylene glycol and/or glycerol are thesolvents used in e-liquids. The e-liquid of e-cigarettes which iscontained in cartridges, for example, contain nicotine contents whichvary widely by brand and brand style. For instance, each JUUL® podcontains 0.7 ml nicotine by volume, which equals 5% nicotine by weight.One JUUL® pod is approximately equivalent, in terms of supplycalculations for any method herein, to 20 cigarettes lasting for about200 puffs. Each brand of e-cigarettes may vary in nicotine content andvolume of e-liquid. The percent of nicotine contained in e-liquid of acartridge, pod, stick (or the like) may be at least the approximatefollowing percentages by weight: 0.25%, 0.50%, 0.75%, 1.0%, 1.25%, 1.5%,1.75%, 2.0% 2.25%, 2.5% 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%,4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75, 7.0%,7.25%, 7.5%, 7.75%, 8.0%, etcetera. Alternatively, the approximateamount of nicotine contained in e-liquid of a cartridge, pod, stick (orthe like) of an e-cigarette may be at least 0.025 ml, 0.05 ml, 0.075 ml,0.10 ml, 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml,0.50 ml, 0.55 ml, 0.60 ml, 0.65 ml, 0.70 ml, 0.75 ml, 0.80 ml, 0.85 ml,0.90 ml, 0.95 ml, 1.00 ml, 1.05 ml, 1.10 ml, 1.15 ml, 1.20 ml, 1.25 ml,etcetera.

E-cigarette devices are sometimes characterized as first generation,second generation or third generation based on their productcharacteristics and features. First generation e-cigarette devices arereferred to as ‘cigalikes’ or vape sticks since they are designed tomimic conventional cigarettes as far as appearance. Second generatione-cigarettes may be characterized by a clearomizer, which is atransparent cartridge that holds e-liquid, an atomizer and a battery.These second-generation devices are comparatively larger than firstgeneration devices and are sometimes referred to as ‘tank systems’ inreference to the transparent reservoir that holds larger amounts ofe-liquid than previous devices. Third generation devices are oftenconsidered ‘vaping products’ and have little resemblance to conventionalcigarettes. These may feature rebuildable and custom atomizers andbatteries.

The latest type or fourth generation e-cigarette utilizes a nicotinesalt and an organic acid. For example, JUUL® pods (cartridges) contain aproprietary salt-based, nicotine, e-liquid formula, which includesbenzoic acid, a naturally occurring ingredient found in tobacco andother substances. When benzoic acid is combined with nicotine salts, ithelps provide increased satisfaction as compared to most e-cigarettes.JUUL® is a closed system, its pods are not designed to be refillable,and JUUL® is rechargeable by way of a USB port.

In some aspects, methods are provided to facilitate smokers who are notinterested in quitting tobacco products altogether to switch fromsmoking conventional nicotine-content combustible cigarettes to usinge-cigarettes or a tobacco heating device. In this methodology, very lownicotine cigarettes are utilized as a bridge between the smoker's usualcigarette brand and e-cigarettes or between the smoker's usual cigarettebrand a tobacco heating device.

In other aspects, a computer or mobile application (App) assists smokersto switch to e-cigarettes or a tobacco heating device with the disclosedmethods and products.

In other aspects, very low nicotine cigarettes comprising enhancedlevels of anatabine and/or anabasine are provided which may be utilizedfor the disclosed methods.

In other aspects, transition kits are provided which comprise of verylow nicotine cigarettes, a tobacco heating device, tobacco sticks, andinformation, instructions and recommendations to assist in switchingsmokers to a tobacco heating device.

In other aspects, transition kits are provided, which include very lownicotine cigarettes, e-cigarettes, and information, instructions andrecommendations to assist in switching smokers to a tobacco heatingdevice.

In other aspects, very low nicotine cigarettes comprising cannabinoidsand/or THC-free cannabis are provided which may be utilized for theaforementioned methods. In this methodology, reconstituted cannabis orreconstituted tobacco including cannabinoids or THC-free cannabis, maybe included in very low nicotine cigarettes.

1. Low Nicotine Tobacco

Various methods may be employed to reduce the nicotine content oftobacco for use in very low nicotine cigarettes. These include plantbreeding techniques, genetic engineering of tobacco lines or tobaccovarieties and/or nicotine extraction from conventional tobacco. Methodsto reduce the nicotine content of tobacco plants, including commercialtobacco varieties used in the production of conventional cigarettes, mayinclude plant breeding techniques. Examples of low nicotine tobaccolines produced by the introduction of two low alkaloid genes (nic1 andnic2 double mutants) from a Cuban cigar tobacco variety into aconventional tobacco variety through a series of backcrosses include LABurley 21, LAFC 53 and LAMD 609. NIC1 and NIC2 loci are two independentgenetic loci in N. tabacum, and nic1 and nic2 mutations independentlyreduce expression levels of nicotine biosynthesis enzymes and nicotinecontent. See, Legg et al., 1969, Journal of Heredity Vol. 60, Issue 4:213-217; Hibi et al. 1994, Plant Cell 6: 723-35; Reed & Jelesko 2004,Plant Science 167(5): 1123-1130.

LA Burley 21 (sometimes referred to as Burley 21 LA) tobacco is agenetically stable breeding line developed and released cooperatively bythe University of Kentucky Agricultural Experiment Station, Lexington,Ky. and Crops Research Division, Agricultural Research Service (ARS) ofthe U.S. Department of Agriculture, Beltsville, Md. LA Burley 21 wasdeveloped by introducing the nic1 and nic2 double mutant genes fromCuban cigar varieties into the Burley 21 variety. The low alkaloidcontent of LA Burley 21 is approximately 0.20% (on a dry weight basis)compared with an average of 3.5% for Burley 21 (a commercial variety atthe time used for cigarettes), which is approximately a 94% reduction.See, Legg et al. 1970, Registration of LA Burley 21 Tobacco Germplasm,Registration No. GP 8, Crop Science Vol. 10, March-April 1970: 212.

LAFC 53 (sometimes referred to as LA 53) is a low-alkaloid, flue-curedtobacco line developed and released cooperatively by the AgriculturalResearch Service (ARS) of the U.S. Department of Agriculture and theNorth Carolina Agricultural Experimental Station. LAFC 53 was developedby backcrossing a low-alkaloid line containing the nic1 and nic2 doublemutants to the NC 95 variety and selecting low alkaloid plants. The linewas released in 1974 to plant breeders, experiment stations, and otherorganizations for research and breeding purposes. LAFC 53 may contain aslittle as approximately 10% of the nicotine content of NC 95 (˜90%reduction), which was a popular commercial flue-cured tobacco variety.See, Chaplin 1975, Registration of LAFC 53 Tobacco Germplasm,Registration No. GP 13, Crop Science, Vol. 15, March-April 1975: 282. RJReynolds Tobacco Company and Philip Morris researched and grew LAFC 53during the 1980s. See, Tobacco Industry Documents, Bates Document No.505348876, Low Nicotine Tobacco 1985 Crop, Chemical Analysis, RJReynolds Tobacco Company; and Tobacco Industry Documents, Bates DocumentNo. 2031403998-2031404044, Mar. 27, 1987, Project 1904, TobaccoPhysiology and Biochemistry, Philip Morris USA.

LAMD 609 is a low alkaloid germplasm line of Maryland tobacco developedby the Maryland Agricultural Experiment Station and released in 1994.LAMD 609 originated from a 1970 cross between LA Burley 21, whichcontains the nic1 and nic2 double mutants, and the MD 609 variety. In a2-year field study in 1991 and 1992 with four replications at the UpperMarlboro Facility of the Central Maryland Research and Education Center,LAMD 609, MD 609, and LA Burley 21 were evaluated for agronomicperformance and chemical content. Averaged over these 2 years, LAMD 609had a total alkaloid content of 0.06%, compared with 1.93% for MD 609,which is approximately a 97% reduction. See, Aycock et al. 1998,Registration of LAMD 609 Tobacco Germplasm, Registration No. GP-52, PI599689, Crop Science, Vol. 38, May-June 1998: 904; Aycock et al. 1997,LAMD 609: A low-alkaloid Maryland tobacco breeding line. University ofMaryland Agronomy Res. Bull ARB-5.

Genetic engineering is a preferred method of producing tobacco having areduced amount of nicotine or an increased amount of anatabine inconjunction with a reduced amount of nicotine. Genetic engineeringincludes any method of introducing a nucleic acid or specific mutationinto a host organism which decreases or increases the expression orfunction of a gene product of interest (i.e., the target gene product).For example, a plant is genetically engineered when it comprises apolynucleotide sequence that, for instance, suppresses expression of agene such that expression of a target gene is reduced compared to acontrol plant. Any enzyme involved in the nicotine biosynthetic pathwaycan be a target for reduced nicotine tobacco lines. Genetic engineeringfor suppressing expression may occur by any method known in the art,such as antisense technology, RNA interference (RNAi), ribozymes, CRISPRtechnology, and microRNAs (miRNAs).

As used herein and relating to tobacco, “down-regulation” or“suppression” are synonymous and mean that expression of a particulargene sequence or variant thereof or nucleotide fragment of at least 15nucleotides of the gene sequence, in a tobacco plant, including forexample progeny plants derived thereof, has been reduced, as compared toa control plant when grown in similar growth conditions, wherein thecontrol plant shares an essentially identical genetic background withthe tobacco plant except for the reduced nicotine alteration in thetobacco plant and any related incidental effects.

In some exemplary embodiments, low nicotine tobacco for use in very lownicotine cigarettes to facilitate smokers switching to e-cigarettes or atobacco heating device is provided by genetically engineering tobaccoplants to comprise a transgene or mutation directly down-regulating theexpression or activity of one or more genes encoding a product such asputrescine N-methyltransferase (PMT), quinolate phosphoribosyltransferase (QPT), N-methylputrescine oxidase (MPO), BBL (BBL enzyme isa flavin-containing oxidase), A622 (A622 enzyme is a member of the PIPfamily of NADPH-dependent reductases), and MATE transporter. Anysuitable method known in the art can be utilized for production of lownicotine tobacco, including sense suppression, sense co-suppression,antisense suppression, RNAi suppression, double-stranded RNA (dsRNA)interference, hairpin RNA interference and intron-containing hairpin RNAinterference, ribozymes, amplicon-mediated interference, smallinterfering RNA, artificial trans-acting siRNA, artificial or syntheticmicroRNA, knock out approaches, random mutagenesis and targetedmutagenesis approaches. For example, the very low nicotine tobaccovariety, Vector 21-41, was developed at North Carolina State Universityby Dr. Mark Conkling utilizing anti sense suppression of QPT (nucleotidesequence set forth in SEQ ID NO: 1 and the amino acid sequence in setforth in SEQ ID NO: 2). See, U.S. Pat. No. 6,586,661. The nicotinecontent of this genetically modified burley variety is approximately0.10%, which is approximately half of the nicotine content of its parentLA Burley 21. See, e.g., U.S. Plant Variety Protection Certificate No.200100039 and Xie et al. 2004 Recent Advances in Tobacco Science,30:17-37.

In some exemplary embodiments, low nicotine tobacco lines or tobaccovarieties are produced (for use in very low nicotine cigarettes tofacilitate smokers switching to an e-cigarettes or tobacco heatingdevice) by introducing non-transgenic mutations into one or morenicotine biosynthetic genes, including but not limited to PMT genefamily, QPT, MPO, BBL gene family including NBB1 and A622, via precisegenetic engineering technologies. The NBB1 nucleotide sequence set forthin SEQ ID NO: 11 and the amino acid sequence in set forth in SEQ ID NO:12. Since numerous obstacles exist to commercialize transgenic tobaccosuch as deregulation requirements of genetically modified crops in theUnited States and other countries, genetically engineering approacheswhich do not result in the low nicotine plant lines containing foreignDNA (DNA not native to Nicotiana plants) are preferable over transgenicapproaches which do result in tobacco containing foreign DNA. Forexample, a mutation breeding approach to identify EMS-induced mutationsin the three most highly expressed isoforms of the BBL gene family weredeveloped at North Carolina State University. Berberine bridgeenzyme-like (BBL) plays a major role in tobacco alkaloid formation. TheBBL enzyme is a flavin-containing oxidase believed to be involved in thefinal oxidation step for nicotine production. The impact of suppressingexpression of the BBL gene family leads to low nicotine phenotypes. See,Kajikawa et al. 2011, Vacuole-Localized Berberine Bridge Enzyme-LikeProteins Are Required for a Late Step of Nicotine Biosynthesis inTobacco, Plant Physiology, April Vol. 155, pp. 2010-2022; Lewis et al.2015, PLOS One, February 17; 10(2): e0117273, both of which areincorporated herein by reference in their entirety.

In other exemplary embodiments, non-transgenic approaches of providinglow nicotine tobacco (for use in very low nicotine cigarettes tofacilitate smokers switching to e-cigarettes or a tobacco heatingdevice) include utilizing random mutagenesis approaches or via precisegenome engineering technologies, for example, transcriptionactivator-like effector nucleases (TALENs), meganuclease, zinc fingernuclease, and CRISPR-cas9 system. See e.g., Gaj et al. 2013, Trends inBiotechnology, 31(7):397-405; Bomgardner 2017, Chemical & EngineeringNews, Vol. 95, Issue 24: 30-34.

In some exemplary embodiments, low nicotine tobacco (for use in very lownicotine cigarettes to facilitate smokers switching to e-cigarettes or atobacco heating device) is provided by genetically engineeringtranscription factors of a tobacco line or variety. A transcriptionfactor is a protein which binds to DNA regions, typically promoterregions, using DNA binding domains and decreases or increases thetranscription of specific genes. A transcription factor negativelyregulates nicotine biosynthesis if expression of the transcriptionfactor decreases the transcription of one or more genes encodingnicotine biosynthesis enzymes and decreases nicotine production. Atranscription factor positively regulates nicotine biosynthesis ifexpression of the transcription factor increases the transcription ofone or more genes encoding nicotine biosynthesis enzymes and increasesnicotine production. Transcription factors are classified based on thesimilarity of their DNA binding domains. See, Todd et al. 2010, Afunctional genomics screen identifies diverse transcription factors thatregulate alkaloid biosynthesis in Nicotiana benthamiana, The PlantJournal 62, 589-600, which is incorporated herein by reference in itsentirety.

In some exemplary embodiments, tobacco lines or varieties aregenetically engineered to comprise one or more non-naturally existingmutant alleles at Nic1 or Nic2 locus, which reduce or eliminate one ormore gene activity from Nic1 or Nic2 locus resulting in low nicotinetobacco for use in very low nicotine cigarettes to facilitate smokersswitching to a e-cigarettes or tobacco heating device. Mutant Nic1 orNic2 alleles can be introduced by any method known in the art includingrandom mutagenesis approaches or via precise genome engineeringtechnologies, for example, transcription activator-like effectornucleases (TALENs), meganuclease, zinc finger nuclease, and CRISPR-cas9system.

The nicotine content of any specific tobacco variety or tobacco lineplanted in a field may vary depending on many factors such as weatherconditions, fertilizer rate, soil conditions and topping practices (theremoval of the tobacco flowers which increases nicotine and othertobacco alkaloids) and growing location. For example, dry weatherconditions generally result in a tobacco crop with a higher nicotinicalkaloid content, including nicotine content. The same commercialtobacco variety planted in the same field for various growing seasonsmay result in nicotine contents of the cured tobacco that can vary by upto approximately forty percent.

In some exemplary embodiments, processes are utilized that extractnicotine from conventional tobacco for use in very low nicotinecigarettes to facilitate smokers switching to e-cigarettes or a tobaccoheating device. These processes are generally costlier compared togrowing tobacco with low nicotine levels since an additional productionprocess is required. For example, a supercritical CO₂ process to removeup to approximately 97% of nicotine from tobacco, which is similar tothe process of producing decaffeinated coffee, has been utilized forcommercial cigarettes test-marketed from 1989 to 1991. It was concludedthat extracting nicotine from tobacco also removed various other tobaccoleaf compounds and components important to tobacco's tastecharacteristics. These incidental extractions include oils and waxes ofthe tobacco plant. Analogous to essential oils in citrus fruit, thepresence and balance of these compounds in tobacco give it thecharacteristic flavor and aroma that is associated with tobacco. Removalof these compounds, or even a change in the concentration ratios, candestroy the characteristic flavor and aroma of the plant. An advantageof the extraction method is that nicotine and other nicotinic alkaloidsthat are extracted from tobacco may be used in other products such ase-cigarettes. See, e.g., Tobacco Industry Documents, Bates Document No.2057908259-2057908291, Sep. 1, 1994, Alkaloid Reduced Tobacco (ART)Program, Philip Morris USA.

2. Assessing and Transitioning Smokers to E-Cigarettes or TobaccoHeating Devices

The Fagerstrom test is a short, convenient self-report measure of aperson's dependency on conventional cigarette smoke. It asks smokers sixmultiple-choice questions. See, Table 3 in The Fagerstrom Test forNicotine Dependence: a revision of the Fagerstrom ToleranceQuestionnaire, British Journal of Addiction (1991) 86, 1119-1127. Basedon a smoker's answers to each of six question, which assigns a scorefrom 0 to 1 for four questions and 0 to 3 for two questions, the scoreresults of the answers to all six questions are added together and thetotal ranges from 0 to 10, and known herein as “dependence score.” Thehigher the value indicates greater dependence on cigarette smoke. Asmoker who scores between 1 and 2 on the Fagerstrom test is consideredto have low dependence, a Fagerstrom score of 3 or 4 is considered lowto moderately dependent, a score of 4 is considered moderatelydependent, and a score of 5 or more is considered highly dependent. SeeHeatherton et al 1991, British Journal of Addiction, 86:1119-1127. Othermethods exist to gauge nicotine dependence such as the 37-item WisconsinInventory of Smoking Dependence Motives (score range is from 11 to 77with higher values indicating greater dependence).

The magnitude of past conventional cigarette usage of a smoker is animportant consideration for extinguishing or changing any positivelyreinforced behavior including methods described herein of transitioninga smoker to e-cigarettes or a tobacco heating device. Conventionalcigarette usage is measured by pack years, which is the number of yearsa person smokes multiplied by the average number of packs smoked per dayover the timeframe the person smoked. For example, a person who smokesabout 1 pack of cigarettes per day (each pack contains 20 cigarettes),and has done so for 15 years, equates to 15 pack years. Ranges of packyears are scored as follows: up to and including five pack years (ratingof 1), more than five pack years up to and including ten pack years(rating of 2), more than ten pack years up to and including fifteen packyears (rating of 3), more than fifteen pack years up to and includingtwenty pack years (rating of 4), more than twenty pack years up to andincluding twenty-five pack years (rating of 5), more than twenty-fivepack years up to and including thirty pack years (rating of 6), morethan thirty pack years up to and including thirty-five pack years(rating of 7), more than thirty-five pack years up to and includingforty pack years (rating of 8), more than forty pack years up to andincluding forty-five pack years (rating of 9), more than forty-five packyears (rating of 10). Smokers of 5 or less pack years (rating of 1) aregenerally more easily converted to e-cigarettes or tobacco heatingdevices, than smokers of twenty-five pack years (rating of 5).

The combination of the Fagerstrom dependence score and the pack-yearrating are added together, known herein as “total smoke dependencescore,” to assist in determining the optimal method and productvariables (as defined below) to switch a smoker to e-cigarettes or atobacco heating device such as switching method, duration of thetransitional period, nicotine level of very low nicotine cigarettes,and/or nicotine level of tobacco sticks for an individual smokerdesiring. For example, smokers with a dependence score of 7 and apack-year rating of 5, which equates to a total smoke dependence scoreof 12, would generally require a longer transitional period than smokerswith a dependence score of 2 and a pack-year rating of 1, which equatesto a total smoke dependence score of 3.

The methods described herein to facilitate smokers to switch toe-cigarettes or a tobacco heating device and the duration of thetransitional period of these methods may vary. Personalized methods ofassisting a smoker to switch to e-cigarettes or a tobacco heating device(which can utilize the computer or mobile App herein) may be determinedby any number of “demographic and tobacco use characteristics” of thesmoker, which may include the smoker's Fagerstrom dependence score,pack-year rating, number of years smoking, packs per day, total smokedependence score, how the smoker first learned about the App, averagenumber of cigarettes smoked per day over the last month, usual cigarettebrand used, any current or previous use of nicotine products includinge-cigarettes, any current or previous use of a tobacco heating product,any current or previous use of any other tobacco products, number ofprevious cigarette quit attempts if any, level of interest in switchingto e-cigarettes or a tobacco heating product compared to level ofinterest in quitting tobacco altogether, marital status, significantother's smoking status and smoking status of any person(s) the smokercohabitates with, gender, age, race, ethnicity, national origin, highestlevel of education attained, occupation, ease of being able to smokeconventional cigarettes, e-cigarettes or a tobacco heating product whileworking. These demographic and tobacco use characteristics are utilizedto construct smoker profiles which may be inputted to a computing systemor device that considers various factors and performs variousoperations.

In this way, the software generates instructions and recommendations fora specific transition regimen and types of products to assist smokerstransitioning to e-cigarettes or a tobacco heating device based on aparticular smoker's information or profile. The term “method and productvariables,” as used herein, include (a) a method to transition smokersto e-cigarettes or a tobacco heating product (e.g., Method A) and anyvariables of the method such as the length of the transitional period,(b) the type, brand and model of e-cigarette (e.g., JUUL® and JUUL podswhich are a closed system not designed to be refillable with e-liquid)or tobacco heating product (holder and tobacco sticks like IQOS® versustobacco heating rods), (c) brand of very low nicotine cigarettes, (d)the product variables for the method during the transitional period (andpotentially after the transitional period) such as nicotine, anatabine,and anabasine content of the very low nicotine cigarettes e-cigarettesor tobacco sticks/heating rods, cannabis content or cannabinoid content,if any, of the very low nicotine cigarettes, e-cigarettes or tobaccosticks/heating rods, and flavorings in the very low nicotine cigarettes,e-cigarettes or tobacco sticks/heating rods, and (e) information,recommendations and instructions for using the method and productsincluding any daily reminders, individualized or personalized aspects,and method of delivery (e.g., via smartphone). Any method used totransition a smoker of conventional cigarettes to e-cigarettes or atobacco heating device may be combined with any product disclosedherein.

The efficacy of the method and product variables is measured based onthe percentage of e-cigarette use or tobacco stick use (or tobaccoheating rod use) and cigarette use, if any, for a period of timegenerally after the transitional period (may also be during thetransitional period) of the transition regimen utilized by the smoker.This measurement period may be any number of days and may start at anytime point. For example, a clinical trial's measurement period may be 1week immediately following the transitional period. There may also beone or more follow-up measurement periods such as 3 months immediatelyfollowing the end of the transitional period and 6 months immediatelyfollowing the end of the transitional period. In some instances, themeasurement period may be during the transitional period such as thelast three days of the transitional period. The three top levels ofswitching efficacy in a clinical trial may be the following: smokersexclusively switching to a tobacco heating product (≥99% and ≤100%tobacco stick use and ≥0 to ≤1% cigarette use), smokers overwhelminglyswitching (≥90% and <99% tobacco sticks and >1% and ≤10% cigarettes),and smokers predominantly switching (≥70% and <90% tobacco sticksand >10% and ≤30% cigarettes). These types of particulars may bedetermined by a regulatory agency such as the U.S. Food and DrugAdministration (FDA) when studies are performed to measure the efficacyof combinations of method and product variables for certain profiles ofsmokers or population subgroups of smokers to assist them intransitioning to e-cigarettes or a tobacco heating product.

“Optimal method and product variables,” as used herein, means thecombination of method and product variables recommended to the smoker,which in most cases give the smoker the highest estimated probability ofswitching to e-cigarettes or a tobacco heating product. The optimalmethod and product variables may be calculated by the computer systemsupporting an App and are based on historical data of smokers with thesame or similar demographic and tobacco use characteristics and thepredictive modeling of machine learning algorithms within the computersystem. Depending on the standard during the measuring period, switchingmeans, for example, ≥70% and <90% tobacco sticks and >10% and ≤30%cigarette use or ≥99% and ≤100% tobacco stick use and ≥0 to ≤1%cigarette use. In some cases, the algorithms may recommend the methodand product variables that may not give the smoker the highestmathematical probability of switching to e-cigarettes or a tobaccoheating product in the interest of having the algorithms learn whichmethod or product variables improves switching rates for a given profileor population subgroup. The measurement period may be any number of daysand may start at any time point. In some exemplary embodiments, theremay be the same method and product variables for a population orsubpopulation of smokers. For example, for a clinical trial forswitching smokers to e-cigarettes or a tobacco heating device, certainarms of the study may all use the same methods and products and the mostefficacious protocol may become a commercial product sanctioned by aregulatory agency or health insurers.

In some exemplary embodiments, the smoker's profile is matched by thecomputer or mobile App to smokers with the most similar demographic andtobacco use characteristics who have used the methods herein andachieved the best switching results such as, for example, those who haveexclusively switched to a tobacco heating device (≥99% and ≤100% tobaccosticks and ≥0 to ≤1% cigarettes), those who have overwhelmingly switched(≥90% and <99% tobacco sticks and >1% and ≤10% cigarettes), and thosewho have predominantly switched (≥70% and <90% tobacco sticks and >10%and ≤30% cigarettes). In other exemplary embodiments, the smoker'sprofile is matched by the computer or mobile App to smokers with themost similar demographic and tobacco use characteristics who have usedthe methods herein and achieved the best switching results such as, forexample, those who have exclusively switched to e-cigarettes (≥99% and≤100% e-cigarette use and ≥0 to ≤1% of previous cigarette use), thosewho have overwhelmingly switched (≥90% and <99% e-cigarette use and >1%and ≤10% cigarette use), and those who have predominantly switched (≥70%and <90% e-cigarette use and >10% and ≤30% cigarette use). The App thenrecommends to the smoker, for example, the type of e-cigarette ortobacco heating product (holder and tobacco sticks versus heating rods)and brand and model, the optimal switching method including duration ofthe transitional period, the required number of tobacco sticks and verylow nicotine cigarettes, and the optimal types of tobacco sticks andvery low nicotine cigarettes in terms of alkaloid profile, flavorings,and whether very low THC cannabis is included. For example, the durationof the transitional period for any method described herein may be atleast 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days, 81 days, 82days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90days, 91 days, 92 days, 93 days, 94 days, 95 days, 96 days, 97 days or98 days. In some exemplary embodiments, the duration of the transitionalperiod may be a fixed number of days for a group of people such as 14days. For example, in determining the ideal method variable or productvariable for the general population of smokers, especially uponlaunching the App, the transitional period for a given method such asMethod A may be fixed. This may assist the predictive modeling of themachine learning algorithms of the App to quickly improve adoption ratesof smokers of aerosol devices.

Generally, dual users of conventional cigarettes and tobacco heatingdevices in studies tradeoff conventional cigarettes for tobacco sticksand vice versa on a one-to-one basis since a cigarette and a tobaccostick deliver roughly the same amount of nicotine to the smoker. Forexample, a dual user who previously smoked 20 conventional cigarettesper day may now smoke 10 conventional cigarettes per day and use 10tobacco sticks per day which equates to 50% cigarette use and 50%tobacco stick use. The number of tobacco sticks required for the methodsherein during the transitional period may be partially based on thenumber of cigarettes smoked per day (e.g., for the last 30 days)multiplied by the number of days in the transitional period. A cushionof extra tobacco sticks by a certain percentage may also be included.For example, if a smoker smokes 25 cigarettes per day, there is a 21-daytransitional period, and an overallotment of 15 percent, at least 604(525+79) tobacco sticks are provided to the smoker. Some types oftobacco sticks or heating rods may deliver to the smoker more or lessnicotine than a conventional cigarette (approximately 1 to 1.5 mg percigarette) in which case the number of tobacco sticks provided to thesmoker is adjusted. For example, a tobacco stick may be capable ofdelivering 20 mg of nicotine per tobacco stick. This tobacco stick wouldbe sufficient for the pack (typically 20 cigarettes) a day smoker to usein about 1 day.

Similarly, for e-cigarettes, depending on the type of e-cigarette, thenumber of e-liquid tanks, cartridges, sticks or pods required for themethods herein may not be on a one-to-one basis like tobacco sticks of atobacco heating product are with conventional cigarettes. For example,JUUL® e-cigarettes require less JUUL® pods per day as compared totobacco sticks. One JUUL® pod, is approximately equivalent to 20cigarettes (in terms of supply calculations for any method herein)lasting for about 200 puffs, which would be sufficient for one day for apack (typically 20 cigarettes) a day smoker. The appropriate adjustmentsare required for supplying a sufficient number of tobacco sticks duringa transitional period (and any follow-up periods) based on the amount ofnicotine in a tobacco stick heating rod, e-liquid tank, e-cigarettecartridge, stick or pod, and the typical usage rates of former smokerswho have exclusively switched to a specific type of aerosol device arealso considered. For example, the supply of JUUL® pod cartridges forMethod A approximately equals the product of the number of conventionalcigarettes the smoker smokes per day, and the number of days in thetransitional period, divided by 20. Therefore, the number of tobaccosticks, heating rods, e-liquid tanks, cartridges, sticks or pods (or thelike) of any aerosol device required for any method herein, may bereferred to as ‘a sufficient number for the transitional period based onthe design of the aerosol device, tobacco heating product, ore-cigarette and the cigarette consumption history of the smoker.

The number of very low nicotine cigarettes required for the methodsherein (during the transitional period and in some instances for aperiod of time after the transitional period) may also be partiallybased on the number of cigarettes smoked per day (e.g., for the last 30days), multiplied by the number of days in the transitional period. Thisproduct is then multiplied by at least 17 percent and the result is theminimum number of very low nicotine cigarettes required for thetransitional period. For example, if a smoker smokes 20 cigarettes perday and there is a 28-day transitional period, at least 95 very lownicotine cigarettes (20*28)*0.17 are provided to the smoker. This numbermay be rounded up to 100 since typically there are 20 cigarettes in apack. The number of 100 cigarettes may be adjusted depending on themethod. For example, a mobile App recommending Method A may require theproduct of cigarettes smoked per day and the number of days in thetransitional period to be multiplied by a percentage greater than 17percent based on the smoker's profile of demographic and tobacco usecharacteristics and demographic and tobacco use characteristics of pastusers of the App. One of the best predictors for the amount of thesetobacco products required is actual use patterns of smokers who haveused the methods and products herein to transition to an aerosol device.

As used herein, a “transition kit” is a package of one or morecompartments, and which includes very low nicotine cigarettes,e-cigarettes, or a tobacco heating device and tobacco sticks (or tobaccoheating rods in place of the tobacco heating device and tobacco sticks),and may include information, recommendations and/or instructions forusing these tobacco products to assist a conventional cigarette smokerto transition to e-cigarettes or a tobacco heating device. A transitionkit may be a single package and delivered to the smoker as a singlepackage, as shown in FIG. 1, or the transition kit may comprise ofmultiple packages. For example, tobacco sticks and very low nicotinecigarettes may be sold or delivered separately or enough tobacco sticksor very low nicotine cigarettes for half of a transitional period may besold or delivered separately. When software-generated information,recommendations or instructions for using the transition kit for MethodA or any other method herein are messaged, texted or emailed to theperson using the method or if the instructions, for example, areconveyed on YouTube® or included on social media platforms such asTwitter® or Facebook®, this may eliminate the need for instructions tobe present in the transition kit. Ideally, all of the components of thetransition kit are included in one package shipped directly to thesmoker desiring assistance to transition to an aerosol device, or theymay all be available at one retail location. This important conveniencefeature allows the smoker greater flexibility to comply with the App'srecommendations and instructions during the stressful transition periodof switching to an aerosol device.

The information, recommendations and instructions for any method hereinof transitioning smokers of conventional cigarettes to e-cigarettes or atobacco heating device may be general for all smokers or populationsubgroups of smokers, but the transition regimen is preferablypersonalized for an individual smoker based on historical data ofsmokers with similar demographic and tobacco use characteristics andpredictive modeling of the machine learning algorithms of a computersystem of a mobile App, as further described below. The information,recommendations and instructions may be in electronic format generatedby a computer system and/or in the form of a hard copy such as a labelplaced on or in the transition kit provided to the smoker containinge-cigarettes or the tobacco heating device and tobacco sticks (orheating rods) and very low nicotine cigarettes. In both instances, theinformation and recommendations may be determined by the computer ormobile App based on input to a computing system that considers variousfactors, including method and product variables (described below), andperforms various operations. These software-generated instructions forthe transitional period (and for a period of time after the transitionalperiod) of a method herein and/or daily instructions pertinent to eachday may be messaged, texted or emailed to the person using the method.

3. Exemplary Hardware and Software Implementations

In other aspects, the present disclosure provides an apparatus,computer-implemented method, and the like for transitioning a smoker ofconventional cigarettes to e-cigarettes or a tobacco heating device. Forinstance, such an apparatus has a communications module (e.g., Ethernetnetwork interface card (NIC), wireless transceiver (Bluetooth, WiFi,etc.)), a storage unit with instructions (i.e., memory), and at leastone processor coupled to the communication module and the storage unitvia one or more buses or wired connections, such that the processor isconfigured to execute instructions. In this regard, the apparatus mayexecute instructions to receive demographic and tobacco use informationof a first smoker; obtain demographic information and tobacco use of asecond smoker, etc.; apply a probabilistic algorithm to portions of thefirst demographic data and compute a value indicative of a likelihoodthat the first smoker transitions from conventional cigarettes toe-cigarettes or a tobacco heating device using each of a plurality ofcandidate products and methods, the candidate products and methods beingcapable of transitioning the first smoker from the conventionalcigarettes to e-cigarettes or a tobacco heating device; select one ofthe candidates for administering to the first smoker based on thecomputed values; and generate and transmit, via the communications unit,a second signal that identifies the selected product or method to thedevice of the first smoker, the second signal comprising informationthat instructs the device to present, within a corresponding interface,data characterizing an administration of the selected product orservice.

Embodiments of the subject matter and the functional operationsdescribed in this specification can be implemented in digital electroniccircuitry, in tangibly-embodied computer software or firmware, incomputer hardware, including the structures disclosed in thisspecification and their structural equivalents, or in combinations ofone or more of them. Embodiments of the subject matter described in thisspecification, including but not limited to, the executable or mobileapplications and application programs described herein, can beimplemented as one or more computer programs, i.e., one or more modulesof computer program instructions encoded on a tangible non-transitoryprogram carrier for execution by, or to control the operation of, a dataprocessing apparatus (or a computer system). Additionally oralternatively, the program instructions can be encoded on anartificially-generated propagated signal, such as a machine-generatedelectrical, optical, or electromagnetic signal that is generated toencode information for transmission to suitable receiver apparatus forexecution by a data processing apparatus. The computer storage mediumcan be a machine-readable storage device, a machine-readable storagesubstrate, a random or serial access memory device, or a combination ofone or more of them.

The terms “apparatus,” “device,” and/or “system” refer to dataprocessing hardware and encompasses all kinds of apparatuses, devices,and machines for processing data, including by way of example aprogrammable processor, a computer, or multiple processors or computers.The apparatus, device, and/or system can also be or further includespecial purpose logic circuitry, such as an FPGA (field programmablegate array) or an ASIC (application-specific integrated circuit). Theapparatus, device, and/or system can optionally include, in addition tohardware, code that creates an execution environment for computerprograms, such as code that constitutes processor firmware, a protocolstack, a database management system, an operating system, or acombination of one or more of them.

A computer program, which may also be referred to or described as aprogram, software, a software application, a module, a software module,a script, or code, can be written in any form of programming language,including compiled or interpreted languages, or declarative orprocedural languages, and it can be deployed in any form, including as astand-alone program or as a module, component, subroutine, or other unitsuitable for use in a computing environment. A computer program may, butneed not, correspond to a file in a file system. A program can be storedin a portion of a file that holds other programs or data, such as one ormore scripts stored in a markup language document, in a single filededicated to the program in question, or in multiple coordinated files,such as files that store one or more modules, sub-programs, or portionsof code. A computer program can be deployed to be executed on onecomputer or on multiple computers that are located at one site ordistributed across multiple sites and interconnected by a communicationnetwork.

The processes and logic flows described in this specification can beperformed by one or more programmable computers executing one or morecomputer programs to perform functions by operating on input data andgenerating output. The processes and logic flows can also be performedby, and apparatus can also be implemented as, special purpose logiccircuitry, such as an FPGA (field programmable gate array) or an ASIC(application-specific integrated circuit).

Computers suitable for the execution of a computer program include, byway of example, general or special purpose microprocessors or both, orany other kind of central processing unit. Generally, a centralprocessing unit will receive instructions and data from a read-onlymemory or a random-access memory or both. The essential elements of acomputer are a central processing unit for performing or executinginstructions and one or more memory devices for storing instructions anddata. Generally, a computer will also include, or be operatively coupledto receive data from or transfer data to, or both, one or more massstorage devices for storing data, such as magnetic, magneto-opticaldisks, or optical disks. However, a computer need not have such devices.Moreover, a computer can be embedded in another device, such as a mobiletelephone, a personal digital assistant (PDA), a mobile audio or videoplayer, a game console, a Global Positioning System (GPS) receiver, or aportable storage device, such as a universal serial bus (USB) flashdrive, to name just a few.

Computer-readable media suitable for storing computer programinstructions and data include all forms of non-volatile memory, mediaand memory devices, including by way of example semiconductor memorydevices, such as EPROM, EEPROM, and flash memory devices; magneticdisks, such as internal hard disks or removable disks; magneto-opticaldisks; and CD-ROM and DVD-ROM disks. The processor and the memory can besupplemented by, or incorporated in, special purpose logic circuitry.

To provide for interaction with a user, embodiments of the subjectmatter described in this specification can be implemented on a computerhaving a display device, such as a CRT (cathode ray tube) or LCD (liquidcrystal display) monitor, for displaying information to the user and akeyboard and a pointing device, such as a mouse or a trackball, by whichthe user can provide input to the computer. Other kinds of devices canbe used to provide for interaction with a user as well; for example,feedback provided to the user can be any form of sensory feedback, suchas visual feedback, auditory feedback, or tactile feedback; and inputfrom the user can be received in any form, including acoustic, speech,or tactile input. In addition, a computer can interact with a user bysending documents to and receiving documents from a device that is usedby the user; for example, by sending web pages to a web browser on auser's device in response to requests received from the web browser.

Implementations of the subject matter described in this specificationcan be implemented in a computing system that includes a back-endcomponent, such as a data server, or that includes a middlewarecomponent, such as an application server, or that includes a front-endcomponent, such as a client computer having a graphical user interfaceor a Web browser through which a user can interact with animplementation of the subject matter described in this specification, orany combination of one or more such back-end, middleware, or front-endcomponents. The components of the system can be interconnected by anyform or medium of digital data communication, such as a communicationnetwork. Examples of communication networks include a local area network(LAN) and a wide area network (WAN) such as the Internet.

The computing system can include clients and servers. A client andserver are generally remote from each other and typically interactthrough a communication network. The relationship of client and serverarises by virtue of computer programs running on the respectivecomputers and having a client-server relationship to each other. In someimplementations, a server transmits data, such as an HTML page, to auser device, such as for purposes of displaying data to and receivinguser input from a user interacting with the user device, which acts as aclient. Data generated at the user device, such as a result of the userinteraction, can be received from the user device at the server.

While this specification contains many specifics, these should not beconstrued as limitations on the scope of the invention or of what may beclaimed, but rather as descriptions of features specific to particularembodiments of the invention. Certain features that are described inthis specification in the context of separate embodiments may also beimplemented in combination in a single embodiment. Conversely, variousfeatures that are described in the context of a single embodiment mayalso be implemented in multiple embodiments separately or in anysuitable sub-combination. Moreover, although features may be describedabove as acting in certain combinations and even initially claimed assuch, one or more features from a claimed combination may in some casesbe excised from the combination, and the claimed combination may bedirected to a sub-combination or variation of a sub-combination.

Similarly, while operations are depicted in the figures in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults. In certain circumstances, multitasking and parallel processingmay be advantageous. Moreover, the separation of various systemcomponents in the embodiments described above should not be understoodas requiring such separation in all embodiments, and it should beunderstood that the described program components and systems maygenerally be integrated together in a single software product orpackaged into multiple software products.

In each instance where an HTML file is mentioned, other file types orformats may be substituted. For instance, an HTML file may be replacedby an XML, JSON, plain text, or other types of files. Moreover, where atable or hash table is mentioned, other data structures (such asspreadsheets, relational databases, or structured files) may be used.

In other embodiments, the present application may use machine learningalgorithms or adaptive processes. Examples of the one or more machinelearning algorithms or adaptive processes include, but are not limitedto, an association-rule algorithm (such as an Apriori algorithm, anEclat algorithm, or an FP-growth algorithm), a clustering algorithm(such as a hierarchical clustering module, a k-means algorithm, or otherstatistical clustering algorithms), a collaborative filtering algorithm(such as a memory- or model-based algorithm), or an artificialintelligence algorithm (such as an artificial neural network). Further,and as described herein, one or more of these machine learningalgorithms or adaptive process may be trained against, and adaptivelyimproved using, certain portions of training data that include, but arenot limited to, data characterizing one or more products and methodsadministered to smokers to transition from conventional cigarettes toe-cigarettes or tobacco heating products and data characterizing asuccess (or failure) of these products and methods.

The present application provides Examples for methodology, apparatuses,devices, products, and the like for facilitating smokers switching fromconventional cigarettes to e-cigarettes or a tobacco heating product.The Examples are illustrative and non-limiting and include variationswithin the spirit of the application.

4. Example 1

Method A—Exemplary Embodiment to Facilitate Smokers Switching toE-Cigarettes or a Tobacco Heating Product

FIG. 1 is a diagram illustrating a method of transitioning cigarettesmokers to a tobacco heating device. As illustrated in FIG. 1, upon asmoker downloading the App 2, the smoker may be asked to answer a seriesof demographic and tobacco use questions to assist in determining aprofile for each smoker, which will be utilized to build the database ofsmoker profiles and for the computer to recommend the optimal method andproduct variables for each smoker. These initial demographic and tobaccouse questions may include, but are not be limited to, questions todetermine a smoker's Fagerstrom dependence score, pack-year rating,total smoke dependence score, how the smoker first learned about theApp, average number of cigarettes smoked per day over the last month,usual cigarette brand used, any current or previous use of nicotineproducts including e-cigarettes, any current or previous use of atobacco heating product, any current or previous use of any othertobacco products, number of previous cigarette quit attempts if any,level of interest in switching to e-cigarettes or a tobacco heatingproduct compared to level of interest in quitting tobacco altogether,significant other's smoking status and smoking status of any person(s)the smoker cohabitates with, gender, age, race, ethnicity, nationalorigin, highest level of education attained, occupation, and ease ofbeing able to smoke conventional cigarettes, e-cigarettes and a tobaccoheating product while working.

An example of a smoker profile is a 37-year-old, Caucasian, American,male smoker of Marlboro® Gold (formerly referred to as Marlboro“Lights”) who first learned about the App from a friend, smokes anaverage of 20 cigarettes per day, has a Fagerstrom dependence score of8, has a pack-year rating of 5 (total smoke dependence score of 13), hasnever tried to quit smoking, does not currently and has neversignificantly used nicotine products in the past other than has triede-cigarettes a few times but has never attempted to switch toe-cigarettes, does not currently and has never previously used tobaccoproducts besides conventional cigarettes and therefore has never had anysignificant dual use of cigarettes and another tobacco product, has ahigh interest in switching to e-cigarettes or a tobacco heating productbut not quitting tobacco altogether, is a high school teacher with amaster of education degree, is not married, can only smoke at lunchtimewhile working, has girlfriend but she does not smoke, and the smokerlives alone.

Based on the smoker's answers to the questions regarding demographic andtobacco use characteristics and the predictive modeling of the machinelearning algorithms, the computer of the mobile App selects the optimaltransition regimen for the smoker. As shown in FIG. 1, this includesMethod A of transitioning smokers of conventional cigarettes with a4-week transitional period 1, which commences at time point zero 3 andends at time point two 4. A transition kit 5 is recommended to thesmoker which includes tobacco sticks of a tobacco heating device. Thesmoker either subsequently agrees to the method and product variables,including an outline of the Method A, and purchases the transition kitor does not. In other exemplary embodiments, the computer of the mobileApp recommends a transition kit for smokers which includes e-cigarettessuch as JUUL® e-cigarettes and pods and not a tobacco heating device.Upon the smoker's confirmation of the method and product variables andthe timeline of the transitional period, the information,recommendations, and instructions 6 for transitioning the smoker toe-cigarettes or a tobacco heating product are delivered to the smoker'ssmartphone based on the smoker's demographic and tobacco usecharacteristics, and the transition kit 5 is shortly thereafter shippedand delivered to the smoker. The smoker may not be required to purchasea transition kit if the smoker is part of a study or other effort tomotivate the smoker to switch.

The information, recommendations, and instructions 6 for Method A inFIG. 1 includes the App's recommendations to the smoker as to the timingof important time points during the transition regimen. For example, theApp will consider a smoker's work schedule among many other factors whendetermining ideal potential time points such as time point zero, whichthe smoker ultimately determines after the App recommends some options.Reminders for upcoming events such as the arrival of the transitionalkit, time point zero, time point one 7, and time point two 4 are sent tothe smoker's smartphone at least once a day throughout the transitionalperiod. Messages of encouragement to follow the recommendations andinstructions of Method A are also regularly sent to the smoker'ssmartphone during and after the transitional period. In this exemplaryembodiment, the information, recommendations and instructions to thesmoker are personalized based on smoker profiles considered and weighedby predictive modeling of the machine learning algorithms of a device,apparatus, and/or computer system. In other embodiments, theinformation, recommendations and instructions may be much more generaland standard for a subgroup of the smoking population.

The exemplary transition kit for the 37-year-old profiled smokerincludes very low nicotine cigarettes containing 1.0 mg of nicotine percigarette and a specific type (brand and model) of tobacco heatingsystem for the 4-week transitional period along with tobacco stickscontaining 4.8 mg of nicotine per tobacco stick, and information andinstructions for Method A to switch the smoker to a tobacco heatingdevice are included in the transition kit delivered to the smoker. Thetransition kit includes enough tobacco products for at least the 4-weektransitional period and potentially for a period of time after thetransitional period. In some exemplary embodiments, components of thetransition kit may each be separately made available to the smoker, forinstance, at a pharmacy or other retail location.

FIG. 3A is a data flow diagram illustrating a system for transitioningcigarette smokers to a tobacco heating device. As shown in FIG. 3A, thedata set collected from each smoker, including the demographic andtobacco use characteristics inputted into the App prior to transitionalperiod of Method A and the smoker's daily tobacco use during thetransitional period (and any measurement periods), is reported by thesmoker via the App and added to the computer system database of smokerprofiles. The smoker's daily tobacco use of very low nicotinecigarettes, e-cigarettes or tobacco sticks (or heating rods), andconventional cigarettes (if any) during the transitional period (andpotentially for a period of time thereafter) is inputted into the App bythe smoker on a daily basis.

As shown in FIG. 1, the protocol of Method A in this exemplaryembodiment instructs the smoker to stop using their usual brand ofconventional cigarettes (and any other conventional cigarettes) at amoment in time, referred to as “time point zero.” 3 Once the smoker hasthe transition kit 4, which includes very low nicotine cigarettes, atobacco heating device and tobacco sticks (or e-cigarettes), and theinstructions and recommendations 6 for Method A, the smoker is directedto schedule time point zero, which commences the transitional period.The duration of the transitional period is outlined in the instructionsand recommendations and the smoker's total smoke dependence score anddemographic and tobacco use characteristics are considered. The optimalmethod and product variables may be calculated by a computer system ofthe App. It is generally recommended to the smoker to schedule timepoint zero 3, at a moment in time, after the last conventional cigarettein the smoker's last pack has been smoked or discarded so that thesmoker does not have any conventional cigarettes. After time point zero,the smoker is directed to smoke the very low nicotine cigarettes withoutrestriction for as long of a period as possible. Without restrictionmeans the smoker may smoke as many very low nicotine cigarettes asdesired and any number of puffs may be taken from each cigarette asdesired by the smoker. There are no limitations. It may be recommendedthat no other tobacco or nicotine product be used during this portion ofthe transitional period.

In this exemplary embodiment, from time point zero 3 through the end ofthe transitional period 1, the smoker is instructed to smoke the verylow nicotine cigarettes without restriction. During the time ofexclusively smoking very low nicotine cigarettes, from time point zeroof the transitional period up to time point one, the smoker isextinguishing the pleasurable and reinforcing effects of combustiblecigarettes. Smoking very low nicotine cigarettes generally reducescraving for conventional cigarettes. The lower the smoker's dependencescore, usually the more likely very low nicotine cigarettes effectivelyreduce craving and the longer period of time a conventional cigarettesmoker can go without smoking a conventional cigarette. The longerperiod of time the smoker can exclusively smoke very low nicotinecigarettes after time point zero, the easier the transition to a tobaccoheating device (or e-cigarettes) will be.

As shown in FIG. 1, the smoker is instructed to start to use the tobaccoheating device (or e-cigarettes) without restriction if and when thesmoker has an overwhelming craving for a conventional cigarette. Anoverwhelming craving may be characterized as such a strong desire tosmoke a conventional cigarette that the smoker's mind is made up orvirtually made up that the smoker needs, and is going to smoke, aconventional cigarette. “Time point one” 7 is referred to as the momentin time the smoker commences using the tobacco heating device (ore-cigarettes). The smoker is instructed to start to use the tobaccoheating device (or e-cigarettes) upon the smoker having an overwhelmingcraving for a conventional cigarette (and to resist smoking aconventional cigarette) since the aerosol from the tobacco heatingdevice (or e-cigarettes) is positively reinforcing to the smoker and toan extent replaces the pleasurable effects of smoke from conventionalcigarettes. This experience is impressionable due to the prior use ofthe very low nicotine cigarettes extinguishing the pleasurable andreinforcing effects of combustible cigarettes. During this timeframe,between time point zero 3 and time point one 7, the very low nicotinecigarettes cause the tobacco heating device (or e-cigarettes) to be morepalatable to the smoker, as compared to the smoker going directly fromconventional cigarettes to a tobacco heating device (or directly toe-cigarettes), which assists the smoker to continue to use the tobaccoheating device (or e-cigarettes).

Between time point zero 3 and time point one 7, it may be recommended tothe smoker to not use any other tobacco product or nicotine product. Ifand when the smoker desires a combustible cigarette between these twotime points and throughout the remainder of the transitional period, thesmoker is directed and urged to smoke a very low nicotine cigarette andnot a conventional cigarette. Each and every time the smoker smokes avery low nicotine cigarette during this timeframe and subsequently usesa tobacco heating product (or adequately satisfying e-cigarette), thesmoker is continuing the process of extinguishing the positive effectsof combustible cigarettes and reinforcing the positive effects of atobacco heating product or e-cigarette. Reminders to use the tobaccoheating device (or e-cigarettes) (without restriction) and very lownicotine cigarettes (without restriction) may be in the form of, forexample, daily messages such as text messages to a smartphone orsmartwatch, alarms, telephone calls or other types of communications. Itmay also be recommended, and reminders may also be sent, that no othertobacco or nicotine product be used during the transitional periodand/or after transitional period. These types of reminders, whether on adaily basis or otherwise, are greatly facilitated and enhanced by thecomputer and mobile App described herein since all the smoker's contactinformation as well as the smoker's demographic and tobacco usecharacteristics are already factored and considered by the computingsystem.

As shown in FIG. 1, the smoker is instructed to cease smoking very lownicotine cigarettes on the last day of the scheduled transitionalperiod, referred to as “time point two,” and to continue to use thetobacco heating device (or e-cigarettes) after the transitional periodwithout smoking any conventional cigarettes. As time point two 4approaches, the smoker is reminded of this date at least on a dailybasis through text messages and these reminders not to smokeconventional cigarettes may continue after the transitional period. Inthis example, the end of the transitional period 1 is exactly 28 daysfrom time point zero, and the smoker is also reminded after thetransitional period to use the tobacco heating device (or e-cigarettes)without restriction and to use the tobacco heating device (ore-cigarettes) exclusively (without other tobacco products). The smokermay be instructed to store any remaining very low nicotine cigarettes inthe refrigerator (so that these cigarettes do not get stale), and toonly smoke these if and when the smoker experiences overwhelming cravingfor a conventional cigarette. If the smoker runs out of very lownicotine cigarettes prior to time point two 4 or additional very lownicotine cigarettes are recommended based on the assessment of thecomputing system, the smoker may be directed to obtain additional verylow nicotine cigarettes in the interest of not smoking any conventionalcigarettes. Very low nicotine cigarette and tobacco sticks (or heatingrods) or e-cigarettes may be ordered through the App at any time and theApp can be set to automatically order any tobacco product such astobacco sticks upon the App user running low.

While the smoker smokes the very low nicotine cigarettes throughout thetransitional period and uses the tobacco heating device (ore-cigarettes) from time point one of the transitional period, very lownicotine cigarettes are extinguishing the pleasurable and reinforcingeffects of combustible cigarettes, and the tobacco heating device (ore-cigarettes) is reinforcing the pleasurable effects of tobacco. By bothof these conditioning principles occurring during the transitionalperiod, smokers transitioning from conventional cigarettes to tobaccoheating devices (or e-cigarettes) is facilitated. As depicted in FIG. 1,it is expected that during the transitional period average tobacco use 8of very low nicotine cigarettes decreases among smokers following MethodA, and while using the aforementioned transition kit and assuming noconventional cigarettes are consumed, average use of tobacco sticks ofthe tobacco heating device (or e-cigarettes) 8 increases to about thesmoker's previous level of conventional cigarettes per day. Replacingcigarette smoke with aerosol from a tobacco heating device ore-cigarettes reduces the levels of harmful and potentially harmfulconstituents (HPHCs) smokers are exposed to and expectedly reduces therisk of tobacco-related disease.

Messages may be sent by the App to the smoker's devices (e.g.,smartphone) leading up to time point zero, throughout the transitionalperiod, and depending on the smoker's level of success of switching to atobacco heating device (or e-cigarettes), potentially for a period oftime after the transitional period. Multiple messages may be sent perday in the interest of the smoker having the highest probability ofswitching to a tobacco heating device (or e-cigarettes). These messagesin terms of their content, frequency and timing are in part based onmatching new users of the App with smokers of similar profiles who havealready successfully used the App in conjunction with the methods andproducts disclosed herein and who have successfully switched to atobacco heating product (or e-cigarettes). For example, the optimalmessage content, how many times to send the message, and the timing ofthe messages for the timeframe between the smoker receiving thetransition kit and time point zero may include the smoker receivingmessages starting when the transition kit is received, and every eighthours thereafter until time point zero. These messages remind andprepare the smoker for time point zero. Subsequent messages from the Appremind and prepare the smoker for other notable events of the protocoland encourage the smoker to follow the recommended protocol in theinterest of becoming smoke free.

Although there are no known published, peer-reviewed results of studiesutilizing very low nicotine cigarettes to transition smokers toe-cigarettes or a tobacco heating product as of the filing of thisapplication, information and results from such studies may also beinputted into, and evaluated by, the computer system related to the Appas they become available. Unlike e-cigarettes which are popular,approximately 99.95 percent of current worldwide smokers has neversmoked a very low nicotine cigarette, and approximately 97 percent ofcurrent worldwide smokers has never used a tobacco heating device.

5. Example 2

Developing Smoker Profiles and Increasing Rates of Smokers Switching toE-cigarettes or a Tobacco Heating Device Through an App

Because the present disclosure provides user generated information forinputting into a computer system, such as pack-year rating, number ofcigarettes smoked per day, etc., the disclosure contemplates a computerand mobile application (App) for conventional cigarette smokers todownload to a smartphone, wearable device, computer or other device tofurther assist conventional cigarette smokers to switch to e-cigarettesor a tobacco heating device using the methods and products disclosedherein. In this regard, databases are first generated and populated withdata and information from studies of smoking behavior, e-cigarettebehavior and tobacco heating device behavior. These include demographicand tobacco use characteristics of smokers in market studies and studiesevaluating dual use of conventional cigarettes and e-cigarettes and dualuse of conventional cigarettes and tobacco heating devices.

As described herein, a “computer or mobile App” or “App” includes anapplication program, script, or one or more elements of compiled codeexecutable by a computing device or computing system operating within acorresponding network environment. Since there are potentially millionsof smoker profiles due to many combinations of demographic and tobaccouse characteristics of the world's approximate one billion smokers, plusan enormous amount of data recorded on the daily use of e-cigarettes ortobacco heating devices, and very low nicotine cigarettes during andafter the transitional period of the methods disclosed herein, it is notpossible for a human to mentally calculate this amount of data andrecommend the optimal method and product variables. These demographicand tobacco use characteristics, along with the daily inputted data oftobacco product use, need to be inputted to a computing system or devicethat has the sufficient computing power to process, analyze and makepredictions from this large amount of data.

The probability of another smoker having the exact smoker profile as theabove 37-year-old male smoker profile is small. The exact probabilitydepends on how questions are asked by the App, the type of questions(e.g., multiple choice questions), and how many choices the smoker hasfor each question. For example, a smoker's occupation can be animportant factor in determining what method the App recommends and thevariables of the method and the variables of the products used for themethod. A multiple-choice question for occupation in which the choicesare white collar or blue collar would be less revealing than a menu inwhich the smoker has dozens of occupation choices. The greater numberquestions and the greater number of potential answers for each questionthat the App asks the smoker, the greater number of potential smokerprofiles and the more differentiated the smoker profile databasebecomes. The greater the differentiation of the database in terms ofdemographic and tobacco use characteristics and daily tobacco use dataduring and after the transitional period, the more effective thepredictive modeling of machine learning algorithms becomes within thecomputer system.

After the smoker answers the required questions and the App calculatesin real time the optimal method and product variables, an order formappears on the screen of the device for the smoker to order thepersonalized transition kit. This includes e-cigarettes or a tobaccoheating device and tobacco sticks for the tobacco heating device, verylow nicotine cigarettes, and highly individualized computer-generatedinformation, including instructions and recommendations for switching aconventional cigarette smoker to e-cigarettes or a tobacco heatingdevice. The tobacco sticks may not be included with the tobacco heatingdevice if there's not a separate holder in which case the heatingelement is contained in each of the tobacco heating rods (e.g., anEclipse® type or a TEEPS® type tobacco heating product described above).The package is then delivered to the smoker by courier or it may bedelivered to a pharmacy or other location where the smoker picks it upand shows identification that the smoker is of the minimum age to usetobacco products.

The computer-generated information, recommendations or instructions forany method to facilitate smokers switching to e-cigarettes or a tobaccoheating product, besides being included in the transition kit providedto the smoker, may also be furnished to the smoker by the App as pop-upmessages or text messages on a smartphone, cellular telephone,smartwatch or other device and may be provided on a daily basis orotherwise. This enhances the effectiveness of the information,recommendations and instructions and efficiently provides any reminders,encouragement, and/or individualized recommendations and instructionsbased on the recommendation of the App and considering the smoker'sdemographic and tobacco use characteristics. For example, for a smokerwith a similar profile of the above 37-year-old male, during the workweek he may have two opportunities per work day to smoke outside whileteaching at school, a 15-minute break at 9:30 AM and an hour lunch breakat 12:30 PM. During the transitional period and even after thetransitional period, the App may send him a text message at these exacttimes reminding him to not smoke conventional tobacco cigarettes anddepending on the stage of the method he in using, to smoke the very lownicotine cigarettes or use the tobacco heating device or e-cigarettes.

In some embodiments, the transition kit, which includes e-cigarettes ora tobacco heating device with tobacco sticks for the tobacco heatingdevice, and very low nicotine cigarettes, may be free of charge, sold atmanufacturer's cost, or deeply discounted compared to retail prices, aslong as the smoker throughout the transitional period, and for a periodof time after the transitional period, inputs the required pertinentinformation into the App or otherwise conveys the pertinent informationto the computing system. This required pertinent information provided bythe smoker includes details on the daily use of the very low nicotinecigarettes and tobacco sticks in the transition kit during thetransitional period or during and after the transitional period for aperiod of time such as 6 months. Any conventional cigarette use mustalso be reported on a daily basis to the computing system. For a free ordeeply discounted transition kit of tobacco products, for example, thesmoker may also have to agree to exchange the tobacco heating device fora new tobacco heating device at some point since some tobacco heatingdevices such as IQOS® have data storage capacity which tracks varioususage information. Even more demanding requirements may include carbonmonoxide (CO), blood and/or urine tests during and/or after thetransitional period to chemically verify the type of and amount oftobacco products the person has been exposed to over certain timeframes.

It is important for smokers using the App to accurately report theirtobacco use during and after the transitional period, which is a reasonfor offering incentives such as free or discounted products to the userof the App. In some cases, the value of this data inputted to thecomputer system through the App is worth the cost of subsidizing theproducts to certain stakeholders such as health insurance carriers. Anyreordering of tobacco sticks or very low nicotine cigarettes through theApp for a period of time can assist in confirming data inputted by theApp user.

All of the data from each smoker using the App is collected and added tothe computer system, including the smoker's profile, the optimal methodand product variables recommended by the App, reordering information,and cigarette and tobacco heating device use (or e-cigarettes use)during and after the transitional period. The level of success of themethod and product variables that the App recommended to the smoker,post transitional period, is compared to the level of success of themethod and product variables that the App recommended to the smokerswith similar smoker profiles, post transitional period. The measurementperiod, which is one or more periods of time typically after thetransitional period of a method to measure the level of switchingsuccess the method and product variables achieved on the smoker, may beany length of time in duration, may start at any time (even during thetransitional period). Examples of measurement periods include 7 daysimmediately after the transitional period and/or 10 days starting 6months after the transitional period. Relevant levels of tobacco useduring a measurement period include (a) smokers who have tried a tobaccoheating product (or e-cigarettes) and no longer use a tobacco heatingproduct (or e-cigarettes), whatsoever, and have gone back to smokingcigarettes, (b) smokers who dually use cigarettes and a tobacco heatingproduct (or dually use cigarettes and e-cigarettes), (c) smokers whohave successfully switched to a tobacco heating product (ore-cigarettes) and exclusively use the tobacco heating product (ore-cigarettes), and (d) smokers who have quit tobacco use altogether.These levels may then be further stratified by the computing system intoeight categories:

(i) smokers who have completely failed to adopt e-cigarettes or atobacco heating product (still smokers: 100% cigarette use),

(ii) smokers who primarily smoke cigarettes (predominant smokers: ≥70%cigarette use and ≤30% tobacco stick use or e-cigarette use),

(iii) smokers who mostly smoke cigarettes (inclined smokers: ≥50% and<70% cigarette use and >30% and ≤50% tobacco stick use or e-cigaretteuse),

(iv) smokers who smoke about the same number of cigarettes as usetobacco sticks or e-cigarettes (half smokers: about 50% cigarette useand about 50% tobacco stick or e-cigarette use),

(v) smokers who mostly use tobacco sticks or e-cigarettes (inclinedtobacco stick or e-cigarette users: ≥50% and <70% tobacco stick ore-cigarette use and >30% and ≤50% cigarette use),

(vi) smokers who primarily use tobacco sticks or e-cigarettes(predominant tobacco stick or e-cigarette users: ≥70% and <90% tobaccostick or e-cigarette use and >10% and ≤30% cigarette use),

(vii) smokers who overwhelmingly use tobacco sticks or e-cigarettes(overwhelming tobacco stick or e-cigarette users: ≥90% and <99% tobaccostick or e-cigarette use and >1% and ≤10 cigarette use), and

(viii) former smokers who have exclusively switched to e-cigarettes or atobacco heating device (exclusive tobacco stick or e-cigarette users:≥99% and ≤100% tobacco stick or e-cigarette use and ≥0 to ≤1% cigaretteuse).

Dual users of conventional cigarettes and tobacco heating devices instudies typically tradeoff conventional cigarettes for tobacco sticksand vice versa on a one-to-one basis. Any replacement of smokingcigarettes with use of tobacco sticks or heating rods is generallybeneficial for health since dual use of smoking cigarettes, whetherconventional and/or very low nicotine, and using a tobacco heatingdevice generally reduces smoke exposure to the smoker, as compared tosmoking only cigarettes and not using a tobacco heating device. Acomplete switch in which the smoker exclusively uses a tobacco heatingdevice is the ultimate goal (short of complete tobacco and nicotinecessation) since a tobacco heating device produces an aerosol withoutany smoke thereby significantly reducing toxins. Any replacement ofsmoking cigarettes with e-cigarette use is also generally beneficial forhealth since dual use of e-cigarettes and conventional cigarettesgenerally reduces smoke exposure to the smoker, as compared to smokingonly cigarettes and not using e-cigarettes.

Proprietary machine learning algorithms work in conjunction with thedatabase of the computing system and identify and calculate significantcorrelations among demographic and tobacco use characteristics of aperson using the App for the first time with those who have already usedthe App and switched to e-cigarettes or a tobacco heating device. Uponlaunching the App and shortly thereafter, the App recommends the optimalmethod and product variables for the new App user which most closelyresemble the most successful method and product variables utilized bythe most similar smoker profile in the database. Subsequently, as moresmokers use the App and provide an increasing number of smoker profilesand switching results from multiple combinations of method and productvariables, predictive modeling algorithms of the App continually improvein successfully switching smokers to a tobacco heating product.

As shown in the App data flow diagram of FIG. 3A, there are variousinputs and outputs within the computer system of the App 9. Afterdownloading the App, a smoker 10 inputs demographic and tobacco usecharacteristics 11 into the App by answering, for example, questions todetermine a smoker's Fagerstrom dependence score, pack-year rating,total smoke dependence score, how the smoker first learned about theApp, average number of cigarettes smoked per day over the last month,usual cigarette brand used, any current or previous use of nicotineproducts including e-cigarettes, any current or previous use of atobacco heating product, any current or previous use of any othertobacco products, number of previous cigarette quit attempts if any,level of interest in switching to e-cigarettes or a tobacco heatingproduct compared to level of interest in quitting tobacco altogether,significant other's smoking status and smoking status of any person(s)the smoker cohabitates with, gender, age, race, ethnicity, nationalorigin, highest level of education attained, occupation, and ease ofbeing able to smoke conventional cigarettes, e-cigarettes, or a tobaccoheating product while working. These inputs occur before the smokercommences utilizing any of the methods and products disclosed herein,and this data is added to the database of the computer system.

As a result of these inputs, the computer system and App identify aseries of outputs to the smoker, as shown in FIG. 3A. These include theoptimal method and product variables 12 for the smoker such as thespecific switching method (e.g., Method A), duration of transitionalperiod, nicotine level of very low nicotine cigarettes, nicotine levelof tobacco sticks, level of very low THC cannabis in the filler of verylow nicotine cigarettes (if any), level of very low THC cannabis in thefiller of the tobacco sticks (if any), and personalized recommendationsand instructions including App reminders and encouragement messages arecontinually reviewed and finetuned. Upon the smoker agreeing to these,the personalized transition kit 13 and information, recommendations andinstructions are forwarded to the smoker.

Another set of inputs occurs after the smoker commences utilizing any ofthe methods and products disclosed herein. As shown in FIG. 3A, thesmoker inputs his or her daily tobacco use 14, including very lownicotine cigarettes, e-cigarettes or tobacco sticks or heating rods, andany conventional cigarette use or other tobacco or nicotine product useduring the transitional period and any measurements periods. Thisinformation being inputted back into the App by the smoker and added tothe database of the computer system is important for the predictivemodeling of machine learning algorithms to improve the effectiveness ofthe transition regimen of the method and product variables to future Appusers. The flow of information throughout the computer system of the Appin FIG. 3A, including product use information during and after thetransitional period, is essentially the same for every App user exceptthe timing of certain timepoints vary based on the method recommendedand the method's variables. As smokers increasingly utilize the App anduse the methods and transition kits herein, the amount of data in thecomputer's database and the accuracy of the machine learning algorithmsin regards to the method and product variables also increase, whichresults in the improving switching rates. As the number of smokerprofiles increases, there is more relevant data on how variouscombinations of method and product variables affect switching resultsfor similar smoker profiles. Also, there is an increased probabilitythat a new user of the App will be matched or closely matched with asmoker profile in the database previously proven to successfullytransition to the tobacco heating device. It is understood that thesingular form of algorithm may also include the plural form ofalgorithms, that is, multiple apps, which are often required forpredictive modeling and analytics.

FIG. 3B is a diagram of an exemplary embodiment of an algorithm matchingprocess for identifying the optimal method and product variables 12 ofFIG. 3A. This process of how the computer identifies the optimal methodand product variables for a new App user is shown in FIG. 3B. The firststep is matching each and every of the dozens of demographic and tobaccouse characteristics of the new App user with the demographic and tobaccouse characteristics of those smokers in the database who have completeda switching method 15 and those smokers in the database who have starteda switching method but have not completed switching method 16. Smokersin the database who have the most similar profile of demographic andtobacco use characteristics may be identified for each of these twogroups. This may be accomplished by matching each demographic andtobacco use characteristic of the new App user with those already in thedatabase who have completed a switching method and a certain percentageof those smokers (e.g., 10%) with greatest number of demographic andtobacco use characteristics to advance to the next step 17. The same isdone for the group who has not completed a switching method 18.Alternatively, each demographic and tobacco use characteristic is givena weight (for example, 10 being the most important and 1 being the leastimportant) and a certain percentage of those smokers in the database whohave completed a switching method with the highest cumulative number ofmatches (e.g., 5%) advance to the next step.

The subset of previous App users who have finished a method may then bestratified into the aforementioned eight categories of switching results(i-viii) from still smokers (i) to former smokers who have exclusivelyswitched to e-cigarettes or a tobacco heating product (viii) 19.Statistically significant relationships among these eight categories andmethod and product variables utilized by former App users are analyzed.Method and product variables include (i) a method to transition smokersto e-cigarettes or a tobacco heating product (e.g., Method A) and anyvariables of the method such as the length of the transitional period,(ii) the type, brand and model of e-cigarette (e.g., JUUL® and JUUL podswhich are a closed system not designed to be refillable with e-liquid)or tobacco heating product (e.g., IQOS® including a holder and tobaccosticks versus tobacco heating rods), (iii) brand of very low nicotinecigarettes, (iv) the product variables for the method during thetransitional period (and potentially after the transitional period) suchas nicotine, anatabine, and anabasine content of the very low nicotinecigarettes, e-cigarettes or tobacco sticks/heating rods, cannabiscontent or cannabinoid content, if any, of the very low nicotinecigarettes, e-cigarettes or tobacco sticks/heating rods, and flavoringsin the very low nicotine cigarettes, e-cigarettes or tobaccosticks/heating rods, and (v) information, recommendations andinstructions for using the method and products including any dailyreminders, individualized or personalized aspects, and method ofdelivery (e.g., via smartwatch).

As shown in FIG. 3B, based on the method and product variables used bythese previous App users who achieved the highest switching rates, inconjunction with considerations of previous smokers who did not completea method and predictive modeling for improving switching rates, optimalmethod and product variables are recommended to the new App user 20. Anyfactors that may have caused smokers to not complete the recommendedtransitional period need to be investigated and addressed sincenon-compliance with the recommended protocol causes reduced switchingrates. An example of predictive learning is that the App may recommend adifferent method variable (e.g., duration of transitional period) and/ora different product variable (e.g., very low nicotine cigarettescomprising 2 mg of nicotine versus 1 mg of nicotine or less) to a newApp user other than those used by the previous App users who achievedthe highest switching rates for a given profile or a given subset ofdemographic and tobacco use characteristics. For example, if 40 year-oldsmokers who (a) have a pack rating of 4, (b) smoke Winston®, (c) haveattempted to quit smoking (defined by purchasing a smoking cessationaid) 2 or 3 times, have better switching results the longer thetransitional period is for Method A and the longest transitional periodrecommended by the App thus far has only been 30 days, the algorithmwill continually recommend a longer transitional period for thesesmokers that have this subset of matching demographic and tobacco usecharacteristics. Upon the switching success rate maximizing for thissubgroup of 40-year-old smokers in terms of length of the transitionalperiod (e.g., 42 days), the App will no longer recommend longertransitional periods and continue to identify other variables to improvethe switching rate for this subgroup.

In this way, the App evolves from initially using only historicalcorrelations among demographic and tobacco use characteristics ofsmokers who have already used the App to utilizing predictive modelingand analytics. The App ‘learns’ by artificial intelligence (AI) theoptimal method and product variables for as many smoker profiles aspossible by using cause and effect as well as historical correlations.Switching rates for each type of smoker profile may be continuallyimproved by optimizing the method and product variables of switchingsmokers to e-cigarettes or a tobacco heating device. New questions indeveloping smoker profiles may also be added or modified periodically inthe interest of further diversifying each smoker profile to improveswitching success rates. The App may also recommend to smokers with asubset of demographic and tobacco use characteristics that overlap adifferent switching method with the same method and product variables tomathematically determine improvements in switching rates.

The App choosing the optimal method and product variables means thecombination of switching method, type of e-cigarettes or tobacco heatingproduct, and other method variables and product variables that haveresulted in the best switching results for smokers that have used theApp which most closely resemble the smoker profile of the new App userat the time. Since there are millions or at least hundreds of thousandsof potential smoker profiles due to many combinations of demographic andtobacco use characteristics, rarely is there an exact match between anew user of the App and previous user of the App.

The optimal method and product variables for a new App user calculatedby machine learning algorithms of the computer system do not necessarilymean the method and product variables which have resulted in smokersexclusively switching to e-cigarettes or a tobacco heating device (≥99%and ≤100% e-cigarettes or tobacco sticks and ≥0 to ≤1% cigarettes), butalso considers smokers who have overwhelmingly switched (≥90% and <99%e-cigarettes or tobacco sticks and >1% and ≤10% cigarettes) and thosewho have predominantly switched (≥70% and <90% e-cigarettes or tobaccosticks and >10% and ≤30% cigarettes) and so on. For example, it may bemore efficacious for the App to recommend a set of method and productvariables which have, for example, a 55 percent probability of a smokerbecoming an overwhelming tobacco stick users (≥90% and <99% tobaccosticks and >1% and ≤10% cigarettes) than for the App to recommend a setof method and product variables which have, for example, a 20 percentprobability of success for the smoker to become an exclusive tobaccostick users (≥99% and ≤100% tobacco sticks and ≥0 to ≤1% cigarettes).These calculations would be evidence based and consider theepidemiological record of comparing different levels of exposure totobacco smoke and aerosol from e-cigarettes or tobacco heating devices.At this time, there is not enough evidence to determine these types oftradeoffs but as more results from studies of e-cigarettes and tobaccoheating devices become available, the more data will be utilized by themachine learning algorithms. Data from peer reviewed studies will beimputed into the computer system of the App and updated regularly.

6. Example 3

Method B—Exemplary Embodiment to Facilitate Smokers Switching toE-Cigarettes or a Tobacco Heating Product

Method B may be more suitable than Method A for certain smokers who havebeen using e-cigarettes or a tobacco heating device in conjunction withtheir usual brand of conventional cigarettes. Unlike new users ofe-cigarettes or a tobacco heating device, these dual users haveexperience in using e-cigarettes and/or a tobacco heating device withconventional cigarettes and may be stratified into the aforementionedseven of eight categories of smokers who have already tried e-cigarettesor a tobacco heating device (ii-viii). Unlike e-cigarettes which arepopular, only about 3 percent of current worldwide smokers haspreviously used a tobacco heating device; however, this number isexpected to increase over time. Method and product variables arepreferably determined by the computing system of an App as describedherein.

FIG. 4 is a diagram illustrating Method B of transitioning cigarettesmokers. This exemplary embodiment may transition a dual user ofconventional cigarettes and e-cigarettes or a dual user of conventionalcigarettes and a tobacco heating device to reduce or eliminate smokeexposure from conventional cigarettes and replace this cigarette usewith aerosol from e-cigarettes or a tobacco heating device. Afterdownloading the App and answering all demographic and tobacco usequestions, the App recommends that the smoker 21, a dual user ofconventional cigarettes and a tobacco heating device, uses Method B witha 6-week transitional period 22, which commences at time point zero 23and ends at time point two 24 (there is no time point one in Method B).Also recommended to the smoker is that very low nicotine cigarettescontaining 1.50 mg of nicotine per cigarette are used and that aspecific type of brand and model of tobacco heating system (may bedifferent than the smoker's usual brand and model of tobacco heatingproduct) is used during the 6-week transitional period along withtobacco sticks containing 6.5 mg of nicotine per tobacco stick. Thesmoker either subsequently agrees to the recommended method and productvariables, including a summary of Method B, and purchases the transitionkit or does not agree. The smoker may not have to purchase anything ifthe smoker is part of a study or other effort to have the smoker switch.In either case, upon the smoker agreeing to the recommended method andproduct variables, the smoker is informed by the App how and when thetransition kit will be delivered to the smoker. Information,recommendations, and instructions 25 for reducing cigarette use andincreasing use of a tobacco heating product are delivered to thesmoker's smartphone based on the smoker's demographic and tobacco useanswers. The transition kit 26 is delivered to the smoker shortlythereafter. This includes the App's recommendations to the smoker ofideal time points to stop smoking conventional cigarettes, including thesmoker's usual brand, which is referred to as time point zero 23, and tocontinue smoking the very low nicotine cigarettes. For example, the Appmay consider a smoker's age, marital status and/or work schedule, amongmany other factors, when determining ideal potential times for timepoint zero, which the smoker ultimately determines after the Apprecommends some options.

If the smoker is a dual user of conventional cigarettes ande-cigarettes, the App may recommend, for example, Method B with a 6-weektransitional period and very low nicotine cigarettes containing 2.00 mgof nicotine and an e-cigarette with a relatively higher nicotine contentthan the smoker's usual brand. Depending on the smoker's usual brand ofconventional cigarettes and tobacco heating product and other factors,the App may recommend e-cigarettes to a dual user of conventionalcigarettes and a tobacco heating product for Method B, and depending onthe smoker's usual brand of conventional cigarettes and e-cigarettes andother factors, the App may recommend a tobacco heating product to a dualuser of conventional cigarettes and e-cigarettes.

Method B may be utilized to replace the smoke portion from the smoker'scigarette use with the aerosol of e-cigarettes or aerosol of a tobaccoheating device, and depending on the level of cigarette use, exclusivelyswitch the dual user to e-cigarettes or a tobacco heating device (≥99%and ≤100% e-cigarettes or tobacco sticks and ≥0 to ≤1% cigarettes),overwhelmingly switch the dual user to e-cigarettes or a tobacco heatingdevice (≥90% and <99% e-cigarettes or tobacco sticks and >1% and ≤10%cigarettes) or predominantly switch the dual user to e-cigarettes or atobacco heating device (≥70% and <90% e-cigarettes or tobacco sticksand >10% and ≤30% cigarettes). As shown in FIG. 4, the protocol ofMethod B directs smokers during the transitional period to stop usingtheir usual brand of conventional cigarettes at a moment in time,referred to as “time point zero,” 23 and to continue to use e-cigarettesor a tobacco heating device. This may be the e-cigarette brand ortobacco heating device brand that the smoker has been using inconjunction with conventional cigarettes or it may be a differente-cigarette brand or tobacco heating device brand with a high nicotinecontent such as one that may be included in a transition kit. Once thesmoker obtains the transition kit 26, which includes very low nicotinecigarettes, e-cigarettes or a tobacco heating device with tobaccosticks, and the information, recommendations and instructions 25 forMethod B, the smoker is directed to schedule time point zero 23, whichcommences the transitional period.

The nicotine content of the e-cigarettes or tobacco sticks in thetransition kit 26 may be higher (than what is typical) for use in anymethod herein including for dual users employing Method B. A highernicotine content e-cigarette or tobacco stick (or tobacco heating rod)used during the transitional period and/or thereafter will likelyfacilitate certain smokers not smoking any conventional cigarettesincluding the smoker's usual brand. The duration of the transitionalperiod, which may be calculated by the computing system of an App, isoutlined in the instructions 25 and depends in part on a smoker'sFagerstrom dependence score, pack-year rating and total smoke dependencescore, current level of dual use (e.g., predominant tobacco stick usewhich is ≥70% and <90% tobacco stick use and >10% and ≤30% conventionalcigarette use), and other factors which may be considered calculated bythe App.

After time point zero 23 during the transitional period, the smoker isdirected to smoke the very low nicotine cigarettes without restrictionand either the e-cigarettes or tobacco heating device withoutrestriction. If and when the smoker desires a combustible cigaretteduring the transitional period (and in some cases after), the smoker isdirected and urged to smoke a very low nicotine cigarette and not anyconventional cigarettes. Reminders to use the e-cigarettes or tobaccoheating device (without restriction) and very low nicotine cigarettes(without restriction) during the transitional period may also be in theform of, for example, daily text messages, telephone calls or othertypes of communications. It may also be recommended, and reminders mayalso be sent that no other tobacco or nicotine product be used duringthe transitional period and/or after transitional period. Theeffectiveness of these types of reminders, whether on a daily basis orotherwise, is greatly enhanced by the App described herein since thesmoker's contact information is known as well as the smoker'sdemographic and tobacco use characteristics.

The smoker is directed to cease smoking very low nicotine cigarettes onthe last day of the scheduled transitional period, defined as “timepoint two,” 24 and to continue to use the either the e-cigarettes ortobacco heating device after the transitional period without smokingconventional cigarettes. As time point two 24 approaches, the smoker mayalso be reminded of this date on a daily basis and these reminders,which may be in the form of messages to smartphone, can continue afterthe transitional period. The smoker may be directed to store anyremaining very low nicotine cigarettes in the refrigerator. Any openedpack could be stored in a plastic bag so the cigarettes do not getstale. These remaining very low nicotine cigarettes should only be usedif and when the smoker experiences overwhelming craving for acombustible cigarette. If the smoker runs out of very low nicotinecigarettes and the smoker believes that the very low nicotine cigarettesmay still be needed, rather than smoking any conventional cigarettessuch as the smoker's usual brand, the smoker may be directed to obtainadditional very low nicotine cigarettes, whether through an App orotherwise.

As shown in FIG. 4, it is expected that during the transitional periodaverage tobacco use 27 of very low nicotine cigarettes decreases amongsmokers following Method B, and assuming no conventional cigarettes aresmoked, average use of e-cigarettes or tobacco sticks 27 of the tobaccoheating device increases to about the smoker's previous cumulative levelof per-day e-cigarettes and conventional cigarettes or tobacco sticksand conventional cigarettes. Replacing cigarette smoke with aerosol frome-cigarettes or a tobacco heating device reduces the levels of harmfuland potentially harmful constituents (HPHCs) smokers are exposed to andexpectedly reduces the risk of tobacco-related disease.

While the smoker smokes the very low nicotine cigarettes and uses thetobacco heating device (or e-cigarettes) throughout the transitionalperiod, very low nicotine cigarettes are extinguishing the pleasurableand reinforcing effects of conventional combustible cigarettes, and thetobacco heating device (or e-cigarettes) is reinforcing the pleasurableeffects of tobacco to a greater extent than when the dual use was withconventional cigarettes and the tobacco heating device (ore-cigarettes). By both of these conditioning principles occurring duringthe transitional period, dual users more easily reduce their smoking ofconventional cigarettes or eliminate their smoking of conventionalcigarettes altogether, and replace their reduced smoking of conventionalcigarettes with increased use of the tobacco heating device (ore-cigarettes). This reduces levels of harmful and potentially harmfulconstituents (HPHCs) smokers are exposed to and expectedly reduces therisk of tobacco-related disease.

7. Example 4

Very Low Nicotine Cigarettes with Enhanced Anatabine and/or AnabasineContent

Anatabine and anabasine share a chemical structure with nicotine, andanatabine and anabasine have been shown to have affinity for nicotinicacetylcholine receptors (nAChRs). Studies on rats have demonstrated thehigher the dose of anatabine, nicotine self-administration decreases,and the lower the dose of anatabine, nicotine self-administrationincreases. Pretreatment with 2.0 mg/kg anatabine significantly reducednicotine self-administration by nearly half. Anabasine displayed abiphasic dose-effect function. Pretreatment with 0.02 mg/kg anabasineresulted in a 25% increase in nicotine self-administration, while 2.0mg/kg of anabasine reduced nicotine infusions per session by over 50%.The elimination half-life of anatabine administered orally to rats isapproximately 2 to 2.5-fold greater than that of nicotine. These resultsshow that anatabine and anabasine can substitute for the subjectiveeffects of nicotine and attenuate withdrawal and craving without theabuse liability of nicotine. See, e.g., Hall et al. 2014, PharmacolBiochem Behav, May; 120: 103-108.

Another exemplary embodiment of the present invention is the use of verylow nicotine cigarettes designed to contain an enhanced content ofanatabine and/or anabasine. Levels of anatabine and/or anabasine in verylow nicotine cigarettes are typical, as compared to that of conventionalcigarettes or even elevated beyond typical levels found in conventionalcigarettes; however, at the very least levels of anatabine and/oranabasine are increased as compared to typical very low nicotinecigarettes used in research studies. There is a need for these types ofvery low nicotine cigarettes with unique proportions of these importantalkaloids found in tobacco, and these cigarettes are especiallyadvantageous when used to assist smokers in switching to e-cigarettes ora tobacco heating device or to assist smokers in quitting tobacco usealtogether. FIG. 5 shows levels of certain minor nicotinic alkaloids inthe filler of the fifty top-selling cigarette brand styles in the UnitedStates. Anatabine content ranges from 0.927 to 1.390 mg/g with a mean of1.1 mg/g. Anabasine content ranges from 0.127 to 0.185 mg/g with a meanof 0.147 mg/g. See, Lisko et al 2013, Anal Chem. March 19; 85(6):3380-3384.

Generally, due to common biosynthetic pathways, there is a highcorrelation of nicotine content, which makes up about 95 percent oftotal alkaloids in the tobacco plant, to anatabine content or anabasinecontent in tobacco varieties and tobacco lines. Tobacco that is low innicotine content (as compared tobacco in conventional cigarettes),including all of the aforementioned tobacco lines with the nic1/nic2double mutants (LA Burley 21, LAFC 53, LAMD 609 and Vector 21-41), isalso relatively low in anatabine and anabasine. For example, six stylesof very low nicotine research cigarettes (NRC 100, NRC 101, NRC 102, NRC103, NRC 104, and NRC 105) distributed for research studies by theNational Institute on Drug Abuse (NIDA) of the National Institutes ofHealth (NIH) under the Nicotine Research Cigarettes Drug Supply Programcontains about 0.40 mg/g of nicotine, 0.0065 mg/g of anatabine and0.0315 mg/g of anabasine in the filler of these cigarettes. See Lisko etal. 2013, von Weymarn et al. 2016, Chem Res Toxicol. March 21; 29(3):390-397, and Notice of Availability of Nicotine Research Cigarettesthrough NIDA's Drug Supply Program, Notice Number: NOT-DA-14-004:

https://grants.nih.gov/grants/guide/notice-files/NOT-DA-14-004.html.Accessed on Jul. 20, 2018.

The nicotine, anatabine and anabasine levels of these very low nicotineresearch cigarettes are lower by 98%, 99% and 79%, respectively,compared to the average nicotine levels of the conventional cigarettebrands in FIG. 2 and the average anatabine and average anabasine levelsof the conventional cigarette brands in FIG. 5. None of theseconventional cigarette brands contain genetically engineered lownicotine tobacco. Typically, the levels of anatabine and anabasine areconcurrently reduced along with nicotine levels in geneticallyengineered tobacco plants by down-regulating expression of a nicotinebiosynthesis gene. For example, suppressing the expression of members ofthe BBL gene family by genetic engineering is another example in whichnicotine, anatabine and anabasine content are concurrently reduced. Insix functioning RNAi tobacco lines, nicotine levels in cured leaf weresignificantly lower (P<0.05) than that observed for the untransformedcontrol line, K326, and these 6 tobacco lines averaged 16 percent of theanatabine content and 70 percent of the anabasine content, as comparedto untransformed control line, K326. See, Lewis et al. 2015, PLOS One,February 17; 10(2): e0117273.

However, an exception to the positive correlation of nicotine contentand anatabine content occurs when a tobacco line is geneticallyengineered by down-regulating the expression of (1) a member of theputrescine N-methyltransferase (PMT) gene family (e.g., nucleotidesequence of PMT1 and PMT2 set forth in SEQ ID NO: 3 and SEQ ID NO: 5)(2)N-methylputrescine oxidase (MPO) (SEQ ID NO: 7) or (3) ornithinedecarboxylase (ODC) (SEQ ID NO: 9), which may result in anatabinecontent being increased while nicotine content is decreased. In fact, insome of the resulting tobacco lines, anatabine levels in the leaf may behigher than nicotine content. See Chintapakom et al. 2003, PlantMolecular Biology 53: 87-105; and U.S. Pat. No. 8,410,341. Althoughthese modifications have been done in tobacco plants to elucidatepathways of secondary metabolites for experimental reasons, and not foruse in tobacco products, the applicant of the present specificationdiscovered that utilizing very low nicotine cigarettes with enhancedlevels of anatabine is an improvement over typical very low nicotinecigarettes, especially for smokers attempting to switch to e-cigarettesor a tobacco heating product or attempting to quit tobacco productsaltogether. Typical very low nicotine cigarettes such as thosedistributed by NIDA contain anatabine levels that are a tiny fraction ofanatabine levels of conventional cigarettes, as demonstrated by Lisko etal. Whether or not the enhanced level of anatabine is fromdown-regulating the expression of the PMT, MPO and/or ODC or addinganatabine from an extrinsic source, very low nicotine cigarettescomprising an enhanced anatabine content are useful to assist inextinguishing the pleasurable and reinforcing effects of conventionalcombustible cigarettes. The PMT1 nucleotide sequence is set forth in SEQID NO: 3 and the amino acid sequence in set forth in SEQ ID NO: 4. ThePMT2 nucleotide sequence is set forth in SEQ ID NO: 5 and the amino acidsequence in set forth in SEQ ID NO: 6. The MPO nucleotide sequence isset forth in SEQ ID NO: 7 and the amino acid sequence in set forth inSEQ ID NO: 8. The ODC nucleotide sequence is set forth in SEQ ID NO: 9and the amino acid sequence in set forth in SEQ ID NO: 10.

As used herein, an “anatabine-enhanced very low nicotine cigarette”means a cigarette containing 2.0 milligrams (mg) or less of nicotine andat least 0.15 mg anatabine. In some exemplary embodiments, an extrinsicsource of anatabine may be utilized and added to the filler of saidcigarette. This source may be plants including tobacco plants with highanatabine in which the anatabine is extracted by, for example, asupercritical CO₂ extraction process. Alternatively, in other exemplaryembodiments, genetically engineered tobacco plants may be used in saidcigarette in which anatabine has been increased, as compared to acontrol plant. In either case, extrinsic anatabine or high anatabineplants may be included in reconstituted tobacco used in the filler ofthe anatabine-enhanced very low nicotine cigarette. The anatabinecontent may also be enhanced by anatabine salts of organic acids,anatabine analogs or synthesized anatabine. Either of these anatabinesources may also be incorporated into reconstituted tobacco used in thefiller of the anatabine-enhanced very low nicotine cigarette. Ananatabine-enhanced very low nicotine cigarette may contain at least thefollowing per-cigarette anatabine contents: 0.15 mg, 0.20 mg, 0.25 mg,0.30 mg, 0.35 mg, 0.40 mg, 0.45 mg, 0.50 mg, 0.55 mg, 0.60 mg, 0.65 mg,0.70 mg, 0.75 mg, 0.80 mg, 0.85 mg, 0.90 mg, 0.95 mg, 1.0 mg, 1.05 mg,1.10 mg, 1.15 mg, 1.20 mg, 1.25 mg, 1.30 mg, 1.35 mg, 1.40 mg, 1.45 mg,1.50 mg, 1.55 mg, 1.60 mg, 1.65 mg, 1.70 mg, 1.75 mg, 1.80 mg, 1.85 mg,1.90 mg, 1.95 mg, 2.0 mg, 2.05 mg, 2.10 mg, 2.15 mg, 2.20 mg, 2.25 mg,2.30 mg, 2.35 mg, 2.4 mg, 2.45 mg, 2.50 mg, 2.55 mg, 2.60 mg, 2.65 mg,2.70 mg, 2.75 mg, 2.80 mg, 2.85 mg, 2.90 mg, 2.95 mg, 3.0 mg, 3.05 mg,3.1 mg, 3.15 mg, 3.20 mg, 3.25 mg, 3.30 mg, 3.35 mg, 3.40 mg, 3.45 mg,3.50 mg, 3.55 mg, 3.60 mg, 3.65 mg, 3.70 mg, 3.75 mg, 3.80 mg, 3.85 mg,3.90 mg, 3.95 mg, 4.0 mg, 4.05 mg, 4.10 mg, 4.15 mg, 4.20 mg, 4.25 mg,4.30 mg, 4.35 mg, 4.40 mg, 4.45 mg, 4.50 mg, 4.55 mg, 4.60 mg, 4.65 mg4.70 mg, 4.75 mg, 4.80 mg, 4.85 mg, 4.90 mg, 4.95 mg or 5.0 mg ofanatabine per cigarette. An advantage of an anatabine-enhanced very lownicotine cigarette is that this type of cigarette reduces withdrawal andcraving of conventional cigarettes more effectively than very lownicotine cigarettes with filler comprising, for example, 0.0065 mg/g ofanatabine. Anatabine-enhanced very low nicotine cigarettes areespecially useful when used to assist smokers in transitioning toe-cigarettes or a tobacco heating device or to assist smokers inquitting tobacco use altogether.

It is important to note that these percentages and others herein whichrefer to the amount of nicotine, anatabine or anabasine contained in acigarette (in milligrams) or in filler (in mg/g or as a percentage) arenot perfectly correlated with the amount of these alkaloids in tobaccoleaf contained in filler. Filler in cigarettes includes tobacco leaf inthe form of cut-rag tobacco but almost always also includes non-tobaccocomponents which do not contain any alkaloids, such as casing,flavorings and a portion of the components that reconstituted tobacco ismade from. These non-tobacco portions of filler reduce the percentage ofalkaloids, including nicotine, anatabine, anabasine and nornicotine infiller, as compared to the percentage of alkaloids of the tobacco leafper se contained in filler (or whole tobacco leaf in which alkaloidlevels are measured independently of filler or before tobacco leafbecomes part of the filler in a cigarette).

As used herein, an “anabasine-enhanced very low nicotine cigarette”means a cigarette containing 2.0 milligrams (mg) or less of nicotine andat least 0.10 mg of anabasine. In some exemplary embodiments, anextrinsic source of anabasine may be utilized and added to the filler ofsaid cigarette. This source may be plants including tobacco plants orplants in which the predominant alkaloid is anabasine such as Nicotianaglauca, Nicotiana noctiflora, Nicotiana petunioides and/or Nicotianadebneyi plants. The anabasine may be extracted by, for example, asupercritical CO₂ extraction process from any type of tobacco. In otherexemplary embodiments, genetically engineered tobacco plants may be usedin anabasine-enhanced very low nicotine cigarettes in which anabasinehas been increased, as compared to a control plant. In either case,extrinsic anabasine or high anabasine plants may be included inreconstituted tobacco used in the filler of the anabasine-enhanced verylow nicotine cigarette. The anabasine content may also be enhanced byanabasine salts of organic acids, anabasine analogs or synthesizedanabasine. Each of these may also be incorporated into reconstitutedtobacco used in the filler of the anabasine-enhanced very low nicotinecigarette. An anabasine-enhanced very low nicotine cigarette may containat least the following per-cigarette anabasine contents: 0.10 mg, 0.12mg, 0.14 mg, 0.16 mg 0.18 mg, 0.20 mg 0.22 mg, 0.24 mg 0.26 mg, 0.28,0.30 mg, 0.32 mg. 0.34 mg, 0.36 mg 0.38 mg, 0.40 mg, 0.42 mg, 0.44 mg,0.46 mg, 0.48 mg, 0.50 mg, 0.52 mg, 0.54 mg, 0.56 mg, 0.58 mg, 0.60 mg,0.62 mg, 0.64 mg, 0.66 mg, 0.68 mg, 0.70 mg, 0.72 mg, 0.74 mg, 0.76 mg,0.78 mg, 0.80 mg, 0.82 mg, 0.84 mg, 0.86 mg, 0.88 mg, 0.90 mg, 0.92 mg,0.94 mg, 0.96 mg, 0.98 mg, 1.0 mg, 1.02 mg, 1.04 mg, 1.06 mg, 1.08 mg,1.10 mg, 1.12 mg, 1.14 mg, 1.16 mg, 1.18 mg, 1.20 mg, 1.22 mg, 1.24 mg,1.26 mg, 1.28 mg, 1.30 mg, 1.32 mg, 1.34 mg, 1.36 mg, 1.38 mg, 1.40 mg,1.42 mg, 1.44 mg, 1.46 mg, 1.48 mg, 1.50 mg, 1.52 mg, 1.54 mg, 1.56 mg,1.58 mg, 1.60 mg, 1.62 mg, 1.64 mg, 1.66 mg, 1.68 mg, 1.70 mg, 1.72 mg,1.74 mg, 1.76 mg, 1.78 mg, 1.80 mg, 1.82 mg, 1.84 mg, 1.86 mg, 1.88 mg,1.90 mg, 1.92 mg, 1.94 mg, 1.96 mg, 1.98 mg or 2.0 mg of anabasine percigarette. An advantage of an anabasine-enhanced very low nicotinecigarette is that this cigarette reduces withdrawal and craving ofconventional cigarettes more effectively than very low nicotinecigarettes with filler comprising, for example, 0.0135 mg/g ofanabasine. Anabasine-enhanced very low nicotine cigarettes areespecially useful when used to assist smokers in transitioning toe-cigarettes or a tobacco heating device or to assist smokers inquitting tobacco use altogether.

A Nicotiana tabacum plant variety or line can be crossed with aNicotiana species in which the predominant alkaloid is anabasine (e.g.,N. glauca). Backcrossing refers to the process in which a progeny plantis repeatedly crossed back to one of its parents. In this case, the‘donor’ parent (N. glauca) refers to the parental plant with the desiredgene or locus to be introgressed, which is high anabasine. The‘recipient’ parent (may be an elite commercialized N. tabacum variety),which can be used one or more times, or ‘recurrent’ parent, which can beused two or more times, refers to the parental plant into which the geneor locus is being introgressed. The initial cross gives rise to the F1generation and the second cross is the F2 generation and so on. Thebackcrossing in this example is performed repeatedly with a progenyindividual of each successive backcross generation being itselfbackcrossed to the same parental genotype. In the above backcrossingscheme, enough generations are produced in order to achieve a tobaccoline that is has a high anabasine content but has as many otherdesirable traits of typical cigarette tobacco, N. tabacum, as reasonablypossible.

Very low nicotine cigarettes comprising an enhanced anatabine contentand an enhanced anabasine content (i.e., “anatabine-enhanced andanabasine-enhanced very low nicotine cigarette”) may contain, forexample, approximately 1.0 milligram nicotine per cigarette,approximately 2.0 mg/g anatabine per cigarette and approximately 0.55mg/g anabasine per cigarette. Assuming the filler of these very lownicotine cigarettes weighs 700 mg per cigarette, the filler of thesecigarettes contains about 1.43 mg/g nicotine, about 2.86 mg/g anatabine,and about 0.79 mg/g anabasine. This anatabine-enhanced andanabasine-enhanced very low nicotine cigarette contains the nicotine ofa very low nicotine cigarette in conjunction with an anatabine contentof approximately a conventional cigarette and an anabasine contentslightly higher than the upper range of a conventional cigarette.Anatabine-enhanced and anabasine-enhanced very low nicotine cigarettesare especially useful when used to assist smokers in transitioning toe-cigarettes or a tobacco heating device or to assist smokers inquitting tobacco use altogether. They may be more effective than ananatabine-enhanced very low nicotine cigarette or an anabasine-enhancedvery low nicotine cigarette.

LAFC 53 which contains approximately a 90 percent nicotine reduction, ascompared to its parent variety, NC 95, as described above, is an exampleof a preferred tobacco line used to produce improved low nicotinetobacco plant lines. As a bona fide flue-cured variety, NC 95 has beengrown for decades and has been used in many commercial products. LAFC 53is a tobacco line which has been naturally bred (nic1/nic2) from NC 95,and therefore is non-transgenic. Importantly, unlike other nic1/nic2 lownicotine lines such as LA Burley 21, LAFC 53 is a flue cured line. Thefiller of virtually all filtered cigarettes either only includesflue-cured cut-rag tobacco or flue-cured cut-rag tobacco is thepredominant type of tobacco in the filler.

In one exemplary embodiment, LAFC 53 is genetically engineered in whichthe expression of putrescine methyltransferase (e.g., PMT1 or PMT2) issuppressed by any of the aforementioned methods. This may beaccomplished by down-regulating PMT via antisense or RNAi technologies,both of which are well known in the art. For example, LAFC 53 istransformed with a binary Agrobacterium vector that carries the 2.0 kbNtQPT1 root cortex specific promoter (or any other suitable plantpromoter) which drives the antisense expression of the NtPMT1 cDNA (orNtPMT2 cDNA). Three hundred independent transformants are allowed toself. Progeny of these plants (T1) are screened for segregation of thetransgene. Progeny of two-thirds of the primary transformants segregate3:1 (a single locus). The remaining one-third progeny segregate atratios of 15:1 or higher (two or more loci). T1 progeny segregating 3:1(resulting from transformation at a single locus) are advanced.

Nicotine and anatabine levels of T1 progeny segregating 3:1 are measuredusing Gas Chromatography. TI progeny that have less than 50% of thenicotine content of the LAFC 53 parent are allowed to self to produce T2progeny. Homozygous T2 progeny are identified by selecting populationsin which 100% of the progeny carried the transgene (heterozygous progenysegregate 3:1). Nicotine and anatabine levels in homozygous andheterozygous T2 progeny are measured using Gas Chromatography to confirmnicotine levels have less than 50% of the nicotine content of the LAFC53 parent. Homozygous T2 progeny of transformants that also have thesame or increased levels of anatabine, as compared to the LAFC 53parent, are allowed to self, producing T3 progeny. T3 progeny are grownand nicotine and anatabine levels are again measured and confirmed. T3progeny of the plant line with the lowest nicotine level and the highestanatabine level are allowed to self, producing T4 progeny. Samples ofthe bulked seeds of T4 progeny are grown and nicotine and anatabine areagain measured and confirmed. This low-nicotine anatabine-enhancedtobacco line is renamed LN-HA. The LN-HA plant line is further fieldtested and compared to its NC 95 parent and another control.

In another exemplary embodiment, LAFC 53 is genetically engineered inwhich the expression of N-methylputrescine oxidase (SEQ ID NO: 7) issuppressed by any of the aforementioned methods. This may beaccomplished by down-regulating MPO via antisense or RNAi technologies.For example, LAFC 53 is transformed with a binary Agrobacterium vectorthat carries the 2.0 kb NtQPT1 root cortex specific promoter (or anyother suitable plant promoter) which drives the antisense expression ofthe NtMPO cDNA. Three hundred independent transformants are allowed toself, and the remainder of the process for these MPO down-regulatedtransformants is exactly the same as the aforementioned methodology forPMT down-regulation and the like known in the art.

In another exemplary embodiment, one or more of the genes in the PMTgene family (e.g., PMT1, SEQ ID NO:5) is knocked out of plants belongingto an elite, conventional-nicotine-content, flue-cured tobacco variety.Considerable progress has been made in targeting proteins to specificDNA sequences in the genomes of live cells. Zinc fingers, TALENS, andCRISPR/CAS9 proteins or protein/RNA complexes are experimentallyamenable to changes in their amino acid sequences or RNA targetingsequences to facilitate their binding to specific DNA sequences. Forexample, and as known in the art, CRISPRs (clustered regularlyinterspaced short palindromic repeats) are DNA loci containing shortrepetitions of base sequences that are present within prokaryotes andfunction as a primitive immune system, cleaving foreign DNA (frominvading viruses). CRISPRs are now used as gene editing tools in manyeukaryotic systems, including plant systems such as models Arabidopsisand Nicotiana. When paired with the Cas9 nuclease, CRISPRs can cleavegenomic DNA in a site-specific manner, thus knocking out geneexpression. Guide RNAs (gRNA or sgRNA) are designed to a specificgenomic sequence, thus directing Cas9 to knockout the gene. Predictivesoftware exists for designing gRNA designs, and for plants, gRNAs aretypically expressed from U6 or U3 promoters, such as the wheat U6promoter; the rice U3 promoter; the maize U3 promoter; or theArabidopsis or rice U6 promoters. For a recent review in plants, seeBortesi and Fischer, 2015, Biotechnology Advances 33(10): 41-52. In thisregard, and as known in the art, an Agrobacterium transformation vectormay be constructed having gRNAs specific for knocking out any of the PMTgene family members, PMT1, PMT2, PMT3, and PMT4, in a recipienttransformed Nicotiana plant. See, e.g., Nekrasov V, Staskawicz B, WeigelD, Jones J D, Kamoun S. Targeted mutagenesis in the model plantNicotiana benthamiana using Cas9 RNA-guided endonuclease. NatBiotechnol. 2013 Aug.; 31(8):691-3.

In another exemplary embodiment, MPO and one or more BBL genes areknocked out of tobacco lines belonging to elite, flue-cured, burley orOriental tobacco varieties with, for example, the CRISPR-cas9 system.Similar to the use of CRISPR/CAS9 system described above for suppressingPMT gene expression, the system may be used for suppressing MPO and/orone or more BBL genes. That is, and as known in the art, anAgrobacterium transformation vector may be constructed having gRNAsspecific for knocking out MPO and/or one or more BBL genes, again usinga plant U6 or U3 promoter, in a recipient transformed Nicotiana plant.The resulting plant lines have reduced MPO and one or more BBL genes,contain the targeted balance of nicotine and anatabine, and are thenutilized for anatabine-enhanced very low nicotine cigarettes which areimprovements over very low nicotine cigarettes without enhanced levelsof anatabine. For example, plant lines which contain approximately 2mg/g nicotine and 2 mg/g of anatabine may be included in very lownicotine cigarettes used for transitioning smokers to a tobacco heatingproduct or for quitting tobacco products altogether.

In another embodiment, NBB1 and MPO may be reduced concurrently in asingle plant line to produce tobacco having reduced nicotine andenhanced anatabine. Suitable tobacco plants include elite, flue-cured,burley or Oriental tobacco varieties, each of which can be geneticallymanipulated using technology known in the art. For example, and in noway limiting, an Agrobacterium transformation vector may be constructedhaving gRNAs specific for knocking out any NBB1 and MPO in single,recipient transformed Nicotiana plant. Tobacco plants are selected thathave reduced nicotine (compared to a control plant) and enhancedanatabine (compared to a low nicotine control plant) for use inproducing tobacco products, such as very low nicotine cigarettes usedfor transitioning smokers to a tobacco heating product or for quittingtobacco products altogether.

Similarly, NBB1 and MPO may be suppressed separately in independentplant lines, and then the resultant cured tobacco may be blended for usein tobacco products. For example, in one plant line, an Agrobacteriumtransformation vector may be constructed having a gRNA specific forknocking out NBB1 in a recipient transformed Nicotiana plant. In aseparate plant line, MPO can be suppressed, for example, using anAgrobacterium transformation vector with a gRNA specific for knockingout MPO. Following selection of a first plant line having suppressedNBB1 (characterized by reduced nicotine compared to a control plant) andselection of a second plant line having suppressed MPO (characterized byreduced nicotine and enhanced anatabine compared to a control plant),cured tobacco from each plant line may be blended together for use in atobacco product, such as a very low nicotine cigarettes used fortransitioning smokers to a tobacco heating product or for quittingtobacco products altogether.

Cured tobacco from these anatabine-enhanced tobacco plant lines (whichmay be registered for plant variety protection) in which one or more ofthe following has been knocked out: PMT, ODC, and/or MPO, may beutilized directly in the filler of anatabine-enhanced very low nicotinecigarettes or the anatabine may be extracted from these tobacco types(e.g., by a supercritical CO₂ extraction process) and incorporated intoreconstituted tobacco which in turn is incorporated intoanatabine-enhanced very low nicotine cigarettes. Additional exemplaryembodiments include filler that is precisely blended to achieve targetedlevels of very low nicotine and targeted levels of enhanced anatabineand/or anabasine. Filler of an anatabine-enhanced and anabasine-enhancedvery low nicotine cigarette comprising targeted levels of nicotine,anatabine and anabasine of 1 mg/g, 2 mg/g, and 1/mg/g, respectively, maybe fabricated by adjusting the alkaloid content of the reconstitutedtobacco based on the alkaloid content of the tobacco that is on hand.For the filler of a cigarette which is 60 percent flue cured tobacco, 20percent burley tobacco, and 20 percent reconstituted tobacco, thenicotine, anatabine and anabasine content of the reconstituted tobaccois adjusted based on the alkaloid content of the flue cured and burleytobacco. With a flue cured tobacco that has a nicotine content of 0.4mg/g, an anatabine content of 0.02 mg/g and an anabasine content of 0.05mg/g and a burley tobacco that has a nicotine content of 1.8 mg/g, ananatabine content of 5 mg/g and an anabasine content of 0.10 mg/g, thereconstituted tobacco is fabricated with 2 mg/g nicotine, 4.94 mg/ganatabine and 4.75 mg/g anabasine. By blending the 60 percent flue curedtobacco, 20 percent burley tobacco, and 20 percent of the incrementallyadjusted reconstituted tobacco, the final filler has a nicotine,anatabine and anabasine content of 1 mg/g, 2 mg/g, and 1/mg/g,respectively, precisely hitting the alkaloid targets. The weight of thecasing and top flavoring of the filler was not considered in thisexample for illustrative purposes but this is easily adjusted for byincreasing the nicotine, anatabine and anabasine levels in thereconstituted tobacco by amounts to make up for the weight of thesenon-tobacco components.

Using this method of blending and adjusting the nicotine, anatabine andanabasine levels of the reconstituted tobacco based on the alkaloidcontent of the tobacco varieties on hand, accordingly, virtually anydesired nicotine, anatabine and anabasine level can be achieved in acigarette. Nicotine, anatabine and anabasine levels in cigarettes willno longer vary based due to the year-to-year variability of the tobaccoharvested and on hand. Precisely blended filler from this method can beincorporated into anatabine-enhanced very low nicotine cigarettes,anabasine-enhanced very low nicotine cigarettes, or anatabine-enhancedand anabasine-enhanced very low nicotine cigarettes and may be includedin transition kits of tobacco products to assist smokers switching toe-cigarettes or a tobacco heating device or for quitting tobacco usealtogether. These types of very low nicotine cigarettes reducewithdrawal and craving of conventional cigarettes more effectively thantypical very low nicotine cigarettes which have extremely low anatabinelevels and extremely low anabasine levels.

8. Example 5

Very Low Nicotine Cigarettes Comprising Cannabinoids or THC-FreeCannabis

Another exemplary embodiment of the present invention is to include verylow THC Cannabis sativa in the filler of very low nicotine cigaretteswhich may be utilized for any method of facilitating smokers to switchto e-cigarettes or a tobacco heating product or to quit tobacco productsaltogether. Very low THC cannabis (as defined below) does not containsignificant levels of Δ9-tetrahydrocannabinol (THC). The speciesCannabis sativa includes both marijuana and hemp. “Cannabis” as usedherein includes C. indica and C. ruderalis which are sometimesconsidered as separate species of C. sativa but herein are consideredtypes of C. sativa and not separate species. Hemp is genetically moresimilar to the indica type of marijuana than to sativa strains.Cannabinoids are the group of more than 100 natural chemical compoundsthat mainly accumulate in female flowers (known as, buds) of cannabisplants. They act on cannabinoid receptors in cells that alterneurotransmitter release in the brain. THC is one of the dozens ofcannabinoids present in cannabis plants. Even though very low nicotinecigarettes containing very low THC cannabis do not contain anysignificant amount of THC, they do contain other cannabinoids, includingcannabidiol (CBD) which shows benefits in treating anxiety anddepression. When smokers cease smoking conventional cigarettes theirlevels of anxiety and depression usually increase; therefore, very lownicotine cigarettes containing very low THC cannabis is beneficial inassisting smokers to switch to e-cigarettes or a tobacco heating deviceor to quit tobacco use altogether. The smoke from very low nicotinecigarettes also containing non-THC cannabinoids is an improvement oversmoke from very low nicotine cigarettes without cannabinoids. Thegreater period of time smokers are able to exclusively smoke very lownicotine cigarettes after time point zero during the transitional periodof the methods herein (while not smoking any conventional cigarettes),the greater probability of switching to e-cigarettes or a tobaccoheating product or quitting tobacco altogether.

The psychoactive effects of THC are primarily mediated by the activationof cannabinoid receptors located throughout the body and are part of theendocannabinoid system, which is involved in a variety of physiologicalprocesses such as mood and appetite. Utilizing cannabis, whethermarijuana stains (which contain higher levels of THC) or hemp strains orvarieties (which contain lower THC levels since hemp has been bred forseed and biomass yield rather than THC), is problematic to include invery low nicotine cigarettes to assist smokers in switching toe-cigarettes or a tobacco heating device or to assist smokers inquitting tobacco altogether since the psychoactive effects of THC wouldinterfere with the daily lives of smokers in that their physical andmental control would be diminished. For example, a smoker attempting toswitch to e-cigarettes or a tobacco heating device would not be able tosmoke very low nicotine cigarettes containing significant levels of THCduring a lunch break while at work without becoming intoxicated andtherefore may not be able to function normally upon returning to workand may become a danger to coworkers. Moreover, employees may fail drugtests if their very low nicotine cigarettes include cannabis containingTHC. Therefore, it is not only useful and advantageous, but a necessity,to include very low THC cannabis (and not conventional cannabis) in verylow nicotine cigarettes (for a subgroup of the smoking population) whichprevents the significant psychoactive effects of THC while retaining thebenefits of the other cannabinoids.

As used herein, “very low THC cannabis” means (i) flowers of a femalecannabis plant, whether or not genetically engineered, which containequal to or less than approximately 1.25 mg/g ofΔ9-tetrahydrocannabinolic acid (THCA) and Δ9-tetrahydrocannabinol (THC),collectively, (ii) the other parts (besides the flowers) of a femalecannabis plant (e.g., leaves) which contain equal to or less thanapproximately 1.25 mg/g of Δ9-tetrahydrocannabinolic acid (THCA) andΔ9-tetrahydrocannabinol (THC), collectively, and/or (iii) all parts of amale cannabis plant which contain equal to or less than approximately1.25 mg/g of Δ9-tetrahydrocannabinolic acid (THCA) andΔ9-tetrahydrocannabinol (THC), collectively. High performance liquidchromatography tandem mass spectrometry (HPLC-MS/MS) may be utilized formeasuring THCA and THC content. See, Aizpurua-Olaizola et al. 2014, AnalBioanal Chem (2014) 406:7549-7560. The aforementioned methods ofmeasuring nicotine content may also be utilized for measuring THCA andTHC content. For example, both gas chromatography and high-performanceliquid chromatography are routinely used in the art for measuring THCAand THC content. See, e.g., Mudge E. et al. 2017, Analytical andBioanalytical Chemistry, 409(12) 3153-3163; Patel et al. 2017, J. PharmBiomed Anal. November 30: 146:15-23. THC is the only plant cannabinoidknown to have clear intoxicating effects on its own. THCV may also haveintoxicating effects, although it is present in very small quantities incannabis strains and varieties and in low doses is believed not to beintoxicating. Down-regulating the expression of genes responsible forthe production of enzymes in the cannabinoid biosynthetic pathway bygenetic engineering reduces THC and THCV.

The cannabinoid biosynthetic pathway in Cannabis sativa is understoodand genetic engineering is an efficient method of producing cannabisplants with no THC or trace levels of THC. Cannabigerolic acid (CBGA) isthe precursor to the three main cannabinoid lines:tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) andcannabichromenic acid (CBCA). During decarboxylation, which occursduring drying and curing of the plant material prior to use and/or uponthe application of heat (e.g., smoking) to the cannabinoid acid, each ofthe following 8 cannabinoid acids: CBGA (Cannabigerolic acid), THCA(Δ9-tetrahydrocannabinolic acid), CBDA (Cannabidiolic acid), CBCA(Cannabichromenenic acid), CBGVA (Cannabigerovarinic acid), THCVA(Tetrahydrocanabivarinic acid), CBDVA (Cannabidivarinic acid) and CBCVA(Cannabichromevarinic acid), converts to and yields the followingcorresponding 8 cannabinoid compounds: CBG (Cannabigerol), THC(Δ9-tetrahydrocannabinol), CBD (Cannabidiol), CBC (Cannabichromene),CBGV (Cannabigerivarin), THCV (Tetrahydrocannabivarin), CBDV(Cannabidivarin) and CBCV (Cannabichromevarin). As cannabis cures andmoisture is reduced, the cannabinoid compounds in their acidic formmature and are slowly converted into related compounds (e.g., THCA toTHC). Curing cannabis over time only causes partial decarboxylation tooccur, which is the reason cannabis flowers generally test positive, forexample, for both THCA and THC (designated herein as THCA/THC). Smokingor vaporizing cannabis will instantaneously decarboxylate cannabinoidsdue to the high temperatures present, making them instantly availablefor absorption through inhalation.

Utilizing genetic engineering to produce very low THC cannabis plantsincludes any method of introducing a nucleic acid or specific mutationinto a host organism which decreases or increases the expression orfunction of a gene product of interest (i.e., the target gene product).For example, a plant is genetically engineered when it is transformedwith a polynucleotide sequence that suppresses expression of a targetgene such that expression of the target gene is reduced compared to acontrol plant. Any enzyme or combination of enzymes involved in thecannabinoid biosynthetic pathway can be a target to reduce THCA for theproduction of a very low THC cannabis plant. For example,down-regulating the expression or activity of one or more genes encodinga product selected from the group consisting of Acyl activating enzyme(nucleotide sequence set forth in SEQ ID NO: 13 and the amino acidsequence in set forth in SEQ ID NO: 14), Olivetol synthase (nucleotidesequence set forth in SEQ ID NO: 15 and the amino acid sequence in setforth in SEQ ID NO: 16), Olivetolic acid cyclase (nucleotide sequenceset forth in SEQ ID NO: 17 and the amino acid sequence in set forth inSEQ ID NO: 18, Aromatic prenyltransferase (nucleotide sequence set forthin SEQ ID NO: 19 and the amino acid sequence in set forth in SEQ ID NO:20), Cannabigerolic acid synthase (CBGAS), Tetrahydrocannabinolic acidsynthase (THCAS) (nucleotide sequence set forth in SEQ ID NO: 21 and theamino acid sequence in set forth in SEQ ID NO: 22), Cannabidiolic acidsynthase (CBDAS) (nucleotide sequence set forth in SEQ ID NO: 23 and theamino acid sequence in set forth in SEQ ID NO: 24), Cannabichromenicacid synthase (CBCAS) (nucleotide sequence set forth in SEQ ID NO: 25and the amino acid sequence in set forth in SEQ ID NO: 26) may beutilized for very low THC cannabis. A genetically engineered plantcharacterized by reduced THCA, as compared to a control plant, isreferred to herein as a reduced THCA cannabis plant. These plants may beutilized to provide very low THC cannabis flowers for use in very lownicotine cigarettes to assist in switching smokers to e-cigarettes or atobacco heating device or quitting tobacco altogether.

Any suitable genetic engineering method known in the art can be utilizedfor production of very low THC cannabis plants, including sensesuppression, sense co-suppression, antisense suppression, RNAisuppression, double-stranded RNA (dsRNA) interference, hairpin RNAinterference and intron-containing hairpin RNA interference, ribozymes,amplicon-mediated interference, small interfering RNA, artificialtrans-acting siRNA, artificial or synthetic microRNA, knock outapproaches, random mutagenesis and targeted mutagenesis approaches.Non-transgenic approaches of providing very low THC cannabis plants arepreferred for use in very low nicotine cigarettes, include utilizingrandom mutagenesis approaches or via precise genome engineeringtechnologies, for example, transcription activator-like effectornucleases (TALENs), meganuclease, zinc finger nuclease, and CRISPR-cas9system. See for example, Gaj et al. 2013, Trends in Biotechnology,31(7):397-405 and Bomgardner Melody M, 2017 Chemical & Engineering News,Vol. 95, Issue 24: 30-34.

Any enzyme involved in the cannabinoid biosynthetic pathway may be atarget for reducing THC in cannabis plants. One or more nucleic acidsthat encode one or more enzymes in the cannabinoid biosynthetic pathwayinclude the following cannabinoid biosynthesis enzymes (polypeptides):Hexanoyl-CoA synthetase (See U.S. Pat. No. 9,546,362), Acyl activatingenzyme (SEQ ID NO: 14, See, Stout et al. 2012, Plant J; 71:353-65),Olivetol synthase (SEQ ID NO: 16, See, Taura et al. 2009, FEBS Lett;583: 2061-6), Olivetolic acid cyclase (SEQ ID NO: 18, See, Gagne et al.2012, P Natl Acad Sci USA; 109: 12811-6), Aromatic prenyltransferase(SEQ ID NO: 20, See, U.S. Pat. No. 8,884,100), Cannabigerolic acidsynthase (See, Fellermeier and Zenk 1998, FEBS Lett; 427:283-5),Tetrahydrocannabinolic acid synthase (SEQ ID NO: 22, See, Sirikantaramaset al. 2004, J Biol Chem; 279:39767-74), Cannabidiolic acid synthase(SEQ ID NO: 24, See, Taura et al. 2007, FEBS Lett; 581: 2929-34),Cannabichromenic acid synthase (SEQ ID NO: 26, See international patentpublication no. WO/2015/196275). The foregoing patents, patentapplication and other references, including the polynucleotides andtheir sequences and polypeptides and their amino acid sequences, areincorporated herein by reference in their entirety. See, Carvalho et al.2017. FEMS Yeast Research, Vol. 17, No. 4, 1-12.

There's usually an inverse relationship between THC and CBD acrosscannabis strains and varieties; the higher the THCA/THC content, thelower the CBDA/CBD content, and the higher the CBDA/CBD content, thelower the THCA/THC content. CBDA/CBD is generally the most abundantcannabinoid combination in hemp stains or varieties. The most abundantcannabinoid combination in most marihuana stains is THCA/THC, either ofwhich on average can be approximately between 10 and 20 percent of theweight of the cannabis flower. While THCA is the more accurate label forcannabis flower that has not been decarboxylated, THCA or THCessentially means the same thing if the flower is going to be smoked,vaporized or heated in some way since heat further converts theremaining THCA to THC.

As used herein and relating to cannabis, “down-regulation” or“suppression” are synonymous and mean that expression of a particulargene sequence or variant thereof or nucleotide fragment of at least 15nucleotides of the gene sequence, in a cannabis plant, including allprogeny plants derived thereof, has been reduced, as compared to acontrol plant when grown in similar growth conditions, wherein thecontrol plant shares an essentially identical genetic background withthe cannabis plant except for the reduced THCV/THC alteration in thecannabis plant and any related incidental effects.

As used herein, “reconstituted cannabis sheet” means a cannabis sheetproduced in the same fashion as reconstituted tobacco sheet in whichcannabis flowers, leaves, dust, stems and/or by-products that have beenpreviously finely ground are then rolled or casted and mixed with acohesive agent or binder and may include humectants, flavors,preservatives, and/or additional cannabinoids or additional terpenes.Reconstituted cannabis sheet does not need to include any tobaccoportions (tobacco and nicotine free) and is easily made intoreconstituted sheets like reconstituted tobacco. The cannabis portion ofthe reconstituted cannabis sheet may be from approximately 70 percent toapproximately 90 percent cannabis, the remainder may be the cohesiveagent or binder, humectants, flavors, preservatives, and/or additionalcannabinoids or additional terpenes. Once fabricated, reconstitutedcannabis sheet is cut in a similar fashion as whole leaf tobacco and the“reconstituted cannabis” may be included in the filler of a cigarette.Alternatively, it may be made commercially available by itself.

As used herein, “reconstituted tobacco and cannabis sheet” means a sheetproduced in the same fashion as reconstituted tobacco sheet in whichtobacco dust, stems and/or by-products and cannabis flowers, leaves,dust, stems and/or by-products (both that have been previously finelyground) are then rolled or casted and mixed together with a cohesiveagent or binder and may include humectants, flavors, preservatives,and/or additional cannabinoids or additional terpenes. Once fabricated,reconstituted tobacco and cannabis sheet is cut in a similar fashion aswhole leaf tobacco and the “reconstituted tobacco and cannabis” may beincluded in the filler of a cigarette. Alternatively, it may be madecommercially available by itself. The tobacco and cannabis portions ofthe reconstituted tobacco and cannabis sheet may be from approximately70 to approximately 90 percent tobacco and cannabis, cumulatively, theremainder 10 to 30 percent may be the cohesive agent or binder,humectants, flavors, preservatives, and/or additional cannabinoids oradditional terpenes. Reconstituted tobacco and cannabis sheet may haveany ratio of tobacco to cannabis such as from 99 percent tobacco to 1percent cannabis all the way to 99 percent cannabis to 1 percenttobacco.

Very low nicotine cigarettes may be specifically designed with targetedlevels of nicotine and targeted levels of very low THC cannabis. Forexample, the filler in very low nicotine cigarettes may be preciselyblended and comprise 82% low nicotine tobacco and 18% very low THCcannabis. The cannabis portion of a very low nicotine cigarette may bedirectly added to the filler or may be included in reconstitutedcannabis sheet or reconstituted tobacco and cannabis sheet. Includingcannabis in either type of reconstituted sheet facilitates preciselyblending the cigarettes with the exact desired ratio of cannabis to lownicotine tobacco and/or the exact desired ratio of nicotine to one ormore cannabinoids (e.g., CBD). Further, this method also improves thecigarette making process since cannabis flowers or leaves, whetherwhole, cut or ground, do not have the shape and form to efficiently passthrough automated cigarette rolling machines (and fill cigarettes)without some retooling of these machines. Reconstituted cannabis sheetor reconstituted tobacco and cannabis sheet, which may include very lowTHC cannabis or any type of cannabis, is made in large sheets (similarto paper) and then may be cut to the exact or similar size and elongatedshape as tobacco cut-rag and for this reason is now easily included incigarettes by automated cigarette rolling machines.

Reconstituted cannabis is easily blended with low nicotine reconstitutedtobacco and low nicotine cut-rag tobacco as three separate fractions ofa filler. Producing reconstituted cannabis separately (tobacco andnicotine free), whether or not very low THC, has distinct advantagesover mixing tobacco portions and cannabis portions into the samereconstituted sheet. These include that the reconstituted sheet iscapable of much higher percentages of cannabis since there is no tobaccoportion in the sheet, and reconstituted cannabis can also function todilute the nicotine content of a type of very low nicotine cigarettessince reconstituted cannabis (whether or not very low THC) containsabsolutely zero nicotine. For example, if the target of filler for atype of very low nicotine cigarette is 0.3 mg/g nicotine and only 0.4mg/g nicotine tobacco is available, blending nicotine-free reconstitutedcannabis at a rate of 25% with 75% low nicotine cut-rag tobacco willyield filler with a nicotine content of 0.30 mg/g nicotine. Sincecannabis is one of the earliest plants to be cultivated and has beenconsumed by humans for millennia, it has a well-known safety profile. Inaddition to the advantages of containing non-THC cannabinoids, very lowTHC cannabis is the ideal non-tobacco/non-nicotine plant for blendingwith tobacco and smoking whether the very low THC cannabis isreconstituted into sheet or used directly in the filler of cigarettes.

Although the cannabis flower (bud) contains the vast majority of thecannabinoids in the female cannabis plant, cannabis leaves and/or stemsmay also be used in reconstituted cannabis sheet and reconstitutedtobacco and cannabis sheet. The leaves may be dried until thechlorophyll is sufficiently reduced. The plant material is first groundinto a powder consistency between approximately 100 mesh andapproximately 400 mesh before introduced into a reconstituted sheetprocess, many of which are known in the art. The reconstituted cannabisor reconstituted tobacco and cannabis may be incorporated in the fillerof cigarettes and either the reconstituted cannabis or reconstitutedtobacco and cannabis may be very low THC cannabis or may be cannabiswith high levels of THC. The filler of a conventional cigarette or of avery low nicotine cigarette may contain any percentage of reconstitutedcannabis or reconstituted tobacco and cannabis including the followingexemplary percentages of reconstituted cannabis or reconstituted tobaccoand cannabis: 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% (percentages are interms of weight).

In another exemplary embodiment, extrinsic extracted cannabinoids orcannabinoids produced outside a cannabis plant (e.g., CBD/CBDA) may beincluded in reconstituted tobacco, reconstituted tobacco/cannabis, orreconstituted cannabis. This allows for exact cannabinoid content andprofiles (i.e., ratio between two individual cannabinoids or ratio amongmore than 2 individual cannabinoids) of individual cannabinoids in anyreconstituted sheet. For example, low nicotine reconstituted tobacco mayinclude CBD/CBDA and CBC/CBCA and have a (CBD/CBDA)/(CBC/CBCA) ratio of10/1, and the source of these cannabinoids may either be extracted fromcannabis or synthesized. See, e.g., U.S. Pat. No. 9,587,212. Very lownicotine cigarettes, tobacco sticks, reconstituted tobacco, ande-cigarettes may comprise at least 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4mg, 1.5 mg, 1.6 mg, 1.7 mg 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9mg, 6.0 mg 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8mg, 6.9 mg, 7.0 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6mg, 8.7 mg, 8.8 mg, 8.9 mg or 9.0 mg of cannabinoids.

Down-regulating the expression of Tetrahydrocannabinolic acid synthase(THCAS) is utilized to provide very low THC cannabis for use in very lownicotine cigarettes. Employing the CRISPR-cas9 system as previouslydescribed, THCAS is suppressed on a hemp variety (e.g., Cherry Wine),which its female flowers contain a high amount of CBDA and a low amountof THCA. A cannabis plant having genetically engineered suppression ofTHCAS and reduced content of THCA/THC may be used in very low nicotinecigarettes, e-cigarettes and tobacco heating products to assist intransitioning smokers away from conventional cigarettes. See,Sirikantaramas et al. 2004, J. Biol. Chem. 279 (38), 39767-39774. Whileany known system for suppressing gene expression may be used, one ofordinary skill in the art could use a CRISPR/CAS9 system, as describedherein for suppressing gene expression. An Agrobacterium transformationvector may be constructed having gRNAs specific for knocking out THCAS,using a suitable plant promoter such as a plant U6 or U3 promoter, in arecipient transformed hemp plant, such as the hemp variety, Cherry Wine.

Regardless of the breeding or genetic engineering method, a cannabisplant, or part thereof, is provided, wherein the level of THCA/THC inthe cannabis plant is reduced to below 1%, below 2%, below 5%, below 8%,below 10%, below 12%, below 15%, below 20%, below 25%, below 30%, below40%, below 50%, below 60%, below 70%, or below 75% of the THCA/THC of acontrol plant when grown in similar growth conditions, wherein thecontrol plant shares an essentially identical genetic background withthe cannabis plant except for the reduced THCA/THC alteration and anyrelated incidental effects. The genetically engineered plant is referredto herein as a THCA/THC reduced cannabis plant.

In another embodiment, the present disclosure provides methodology forreducing Δ9-tetrahydrocannabinolic acid (THCA/THC) in a cannabis plantand utilizing said plant in very low nicotine cigarettes for assistingsmokers to switch to e-cigarettes or a tobacco heating product or toquit tobacco use altogether. A THCA/THC reduced cannabis plant alsofinds uses in any type of tobacco or cannabis formulation or productsuch as e-cigarettes, conventional cigarettes, and tobacco sticks ortobacco heating rods. As known in the art, any methodology for reducinggene expression may be used, such as but not limited to antisensetechnology, RNA interference (RNAi), ribozymes, CRISPR technology, andmicroRNAs (miRNAs).

Any very low nicotine cigarette, conventional cigarette, e-cigarette,tobacco stick or tobacco heating rod may each contain at least thefollowing very-low-THC cannabis amounts: 2 mg, 3 mg, 5 mg, 10 mg, 20 mg,40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg 380 mg, 400mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 920 mg, 940mg, 960 mg, 980 mg, 1000 mg, 1.020 g, 1.040 g, 1.060 g, 1.080 g, 1.100g, 1.120 g or 1.140 g. These tobacco products, including conventionalcigarettes that contain more than 2 mg of nicotine (e.g., 3 mgnicotine), may be used for transitioning smokers away from typicalnicotine-content conventional cigarettes such as those in FIG. 2. Anycannabis plant part such as flowers or leaves may be included in thesetobacco products and other tobacco products. The above cannabis amounts,2 mg though 1.140 g, may also be in the form of reconstituted cannabis(including the non-cannabis fractions of any reconstituted cannabisprocess) or reconstituted tobacco and cannabis (including thenon-cannabis and non-tobacco fractions of any reconstituted tobacco andcannabis). Reconstituted tobacco, reconstituted cannabis, orreconstituted tobacco and cannabis may include extracted cannabinoids orsynthetic cannabinoids produced outside of a cannabis plant (e.g., CBD).

Δ9-tetrahydrocannabinolic acid (THCA) can be reduced in a cannabis plantby suppressing expression of Tetrahydrocannabinolic acid synthase(THCAS) in the plant as well as suppressing at least one additionalcannabinoid biosynthesis enzyme. THCAS, as set forth in SEQ ID NO: 21,and one or more cannabinoid biosynthesis genes (SEQ ID NOS: 13, 15, 17,19, 21, 23, 25) may be suppressed concurrently in a single plant line toproduce cannabis with reduced THCA/THC. In addition, THCAS andCannabigerolic acid synthase (CBGAS) may be concurrently suppressed incannabis plants along with suppression of at least one additionalcannabinoid biosynthesis enzyme selected from the following group: Acylactivating enzyme, Olivetol synthase, Olivetolic acid cyclase, Aromaticprenyltransferase, Tetrahydrocannabinolic acid synthase, Cannabidiolicacid synthase (CBDAS) and Cannabichromenic acid synthase (CBCAS). Anysuitable method of plant genetic engineering may be used, as known inthe art.

Suitable cannabis plants can be any elite Cannabis sativa strain orvariety, each of which can be genetically manipulated using technologyknown in the art. For example, and in no way limiting, an Agrobacteriumtransformation vector may be constructed having gRNAs specific forknocking out THCAS and another cannabinoid biosynthesis gene in single,recipient transformed Cannabis sativa plant. Cannabis plants areselected that have reduced THCA/THC (compared to a control plant) foruse tobacco or nicotine products, such as very low nicotine cigarettesused for transitioning smokers to e-cigarettes or a tobacco heatingproduct, to reduce a smoker's nicotine exposure or for quitting tobaccoproducts altogether. Very low THCA/THC cannabis plant parts (e.g.,cannabinoids) may also be incorporated into the e-liquid of e-cigarettesor the tobacco in a tobacco stick of a tobacco heating product.

Similarly, expression of THCAS and another cannabinoid biosynthesis genemay be suppressed separately in independent plant lines, and then theresultant cannabis may be blended together for use in tobacco products.For example, in one plant line, an Agrobacterium transformation vectormay be constructed having a gRNA specific for knocking out THCAS in arecipient transformed Cannabis sativa plant. In a separate plant line,another cannabinoid biosynthesis gene can be suppressed, including anyof the aforementioned cannabinoid biosynthesis genes, for example, usingan Agrobacterium transformation vector with a gRNA specific for knockingout this gene. Following selection of a first plant line havingsuppressed THCAS (characterized by reduced THCA/THC compared to acontrol plant) and selection of a second plant line having suppressedactivity (characterized by low THCA/THC compared to a control plant),cannabis buds from each plant line may be blended together for use in atobacco product, such as a very low nicotine cigarettes used fortransitioning smokers to a tobacco heating product, reducing nicotineexposure, or for quitting tobacco products altogether. These buds ofother plant parts may be incorporated into reconstituted cannabis orreconstituted tobacco and cannabis.

9. Example 6

Method a Clinical Trial Protocol Evaluating Very Low Nicotine Cigaretteswith and without Very Low THC Cannabis to Facilitate Switching to IQOS®Heating System or to JUUL® e-Cigarettes

FIG. 6 is a diagram illustrating a clinical trial protocol oftransitioning cigarette smokers to e-cigarettes or a tobacco heatingdevice, according to the method of FIG. 1. Criteria for being recruitedinto the 4-arm study include smokers who are not interested in quittingtobacco and smokers who have never extensively used very low nicotinecigarettes, e-cigarettes, or a tobacco heating device. Unlikee-cigarettes which are popular, approximately 99.95 percent of currentworldwide smokers has never smoked a very low nicotine cigarette, andapproximately 97 percent of current worldwide smokers has never used atobacco heating device.

In this contemplated trial, the 6-week transitional period 28 is fixedfor all subjects in the four arms of the trial, and the nicotine levelof the tobacco sticks is the same for all the subjects using tobaccosticks in the study, and the nicotine level of the e-cigarettes is thesame for all the subjects using e-cigarettes in the study. The totalnumber of subjects is anticipated to be at least twelve hundred smokers.The timeframe leading up to the transitional period includes,recruitment, screening and randomization 29 of the subjects into thefour arms. After randomization is complete, the App is downloaded 30 bythe subjects' then information, recommendations and instructions 31 aresent to the smokers' smartphone and the smokers are supplied with theirtransition kits 32. Four hundred subjects will be in the first arm ofthe study and use very low nicotine cigarettes containing approximately0.67 mg of nicotine per cigarette, and half of these subjects will usethe IQOS® heating system and half will use JUUL® electronic cigarette.Four hundred subjects will be in the second arm and use very lownicotine cigarettes containing 80 percent low nicotine tobacco (samefiller as cigarettes in first arm) and 20 percent reconstitutedcannabis, which comprises 75 percent very low THC cannabis and 25percent non-cannabis, non-tobacco fractions of the reconstitutedcannabis process, and half of these subjects will use the IQOS® heatingsystem and half will use JUUL® electronic cigarette. The very lownicotine cigarettes in the second arm therefore contains about 0.54 mgof nicotine per cigarette. The two hundred subjects in the third arm andthe two hundred subjects in the fourth arms will not use any very lownicotine cigarettes so none are included in the clinical trial materialsdistributed to them.

As shown in FIG. 6, the 6-week treatment period (transitional period) 28is followed by a 4-week measurement period 33 and a 1-week follow-upmeasurement period 34 to determine cigarette and tobacco stick useacross the four arms of the study. The 1-week follow-up measurementperiod 34 commences six months from time point zero 35 to furtherevaluate tobacco use over this seven-day period. The subjects in thefirst and second arms follow the same general instructions andrecommendations as the Method A exemplary embodiment of FIG. 1. Subjectsstop smoking conventional cigarettes at time point zero 35 and startsmoking very low nicotine cigarettes. They start using either the IQOS®heating system or JUUL® electronic cigarettes at time point one 36 (uponoverwhelming craving) and stop smoking the very low nicotine cigarettesat time point two 37 and continue to use IQOS® or JUUL® after thetransitional period.

The subjects in the third arm are instructed to start using the IQOS®heating system at time point zero 35 (the same time point the subjectsin the first and second arms stop smoking conventional cigarettes andstart smoking the very low nicotine cigarettes) and not to smokecigarettes of any type. These subjects are also instructed to continueto use IQOS® throughout the 6-week transitional period and the 4-weekmeasurement period. The subjects in the fourth arm are instructed tostart using the JUUL® electronic cigarettes at time point zero 35 andnot to smoke cigarettes of any type. These subjects are instructed tocontinue to use JUUL® throughout the 6-week transitional period and the4-week measurement period.

The primary endpoint of this Method A clinical trial across the fourarms is, for example, to exclusively or overwhelmingly use tobaccosticks or e-cigarettes (≥90% and ≤100% tobacco stick use or e-cigaretteuse and ≥0 to ≤10% cigarette use) over the 4-week and one-weekmeasurement periods shown in FIG. 6. Switching rates, including usagerates of tobacco sticks and cigarettes and e-cigarettes and cigarettes,are evaluated during transitional period and measurement periods and arecompared across the four arms of the study. Daily cigarette use (verylow nicotine and conventional, if any), daily tobacco stick use, anddaily e-cigarette use are counted, tracked and inputted into the App byeach subject during the transitional period, 4-week measurement periodand the 1-week follow-up measurement period.

What is claimed is:
 1. Reconstituted cannabis made from a cannabis plantin which Δ9-tetrahydrocannabinolic acid has been reduced, as compared toa control cannabis plant, by down-regulating the expression oftetrahydrocannabinolic acid synthase (SEQ ID NO: 21) in cannabis plants.2. A very low nicotine cigarette comprising the reconstituted cannabisof claim
 1. 3. An apparatus, comprising: a communications module; astorage unit storing computer-readable instructions; and at least oneprocessor coupled to the communications module and the storage unit, theat least one processor being configured to execute the computer-readableinstructions to: receive, via the communications unit, a first signalfrom a device of a first smoker, the first signal comprising firstdemographic data characterizing the first smoker and usage datacharacterizing tobacco use by the first smoker; in response to receivingthe first signal, obtain profile data associated with respective one ormore second smokers, the profile data comprising (i) second demographicdata characterizing the respective second smokers and (ii) program dataidentifying a product and method utilized by the respective secondsmokers to transition from conventional cigarettes to an aerosol device;based on an application of a probabilistic algorithm to the firstdemographic data, the usage data, and the profile data, compute a valueindicative of a likelihood that the first smoker transitions from theconventional cigarettes to the an aerosol device using each of aplurality of candidate products and methods for administration to thefirst smoker capable of transitioning the first smoker from theconventional cigarettes to the tobacco an aerosol device from among theprogram data identifying a product and method utilized by the respectivesecond smokers to transition from conventional cigarettes to an aerosoldevice; select one of the candidate products and methods foradministration to the first smoker based on the computed values; andtransmit, via the communications unit, a second signal that identifiesthe selected product and method for administration to the first smokerto the device of the first smoker for the device of the first smoker topresent, in a user interface, information characterizing anadministration of the selected product and service for administration tothe first smoker for transitioning the first smoker from theconventional cigarettes to an aerosol device.
 4. The apparatus of claim3, wherein: the storage unit stores a database maintaining the profiledata; and the at least one processor is further configured to obtain,from the database, a portion of the profile data associated with the oneor more second smokers in response to receiving the first signal.
 5. Theapparatus of claim 4, wherein the at least one processor is furtherconfigured to identify the candidate products and methods foradministration to the first smoker based on the portion of the profiledata.
 6. The apparatus of claim 3, wherein the probabilistic algorithmcomprises at least one of a statistical process or a machine learningalgorithm.
 7. The apparatus of claim 3, wherein: the first demographicdata comprises age or sex; and the second demographic data comprises ageor sex.
 8. The apparatus of claim 7, wherein the usage data comprisesnumber of years smoking or number of cigarettes per day.
 9. Theapparatus of claim 8, wherein the at least one processor is furtherconfigured to select the one of the candidate products based on acomparison of the first and second demographic data.
 10. The apparatusof claim 3, wherein the at least one processor is further configured to:select the one of the candidate products and method for administrationto the first smoker based on a maximum value among the for each of theplurality of candidate products and methods for administration to thefirst smoker capable of transitioning the first smoker from theconventional cigarettes to an aerosol device.
 11. A system fortransitioning a smoker from cigarette smoking to an aerosol device, thesystem comprising: a memory storing a database of smoker profilesrespectively in association with method and product variables oftransition regimens for transitioning smokers from cigarette smoking toan aerosol device, each smoker profile comprising demographic andtobacco use characteristics of the respective smokers; and a processorconfigured to execute a program for a method of providing a recommendedtransition regimen for transitioning a smoker from cigarette smoking toan aerosol device, the method comprising: receiving demographic data ofthe smoker and tobacco usage data of the smoker; determining demographiccharacteristics and tobacco use characteristics of the smoker, based onthe demographic data of the smoker and the tobacco usage data of thesmoker; determining one or more smoker profiles in the database havingdemographic and tobacco use characteristics of the respective smokerssimilar to the demographic characteristics and tobacco usecharacteristics of the smoker; determining method and product variablesof a transition regimen for transitioning the smoker from cigarettesmoking to an aerosol device based on the product variables oftransition regimens for transitioning the smokers from cigarette smokingto an aerosol device; and providing, to the smoker, the transitionregimen for transitioning the smoker from cigarette smoking to anaerosol device.
 12. The system of claim 11, wherein the respectivesmokers comprise smokers successfully transitioning from cigarettesmoking to the tobacco an aerosol device, smokers currentlytransitioning from cigarette smoking to an aerosol device, and smokersunsuccessfully transitioning from cigarette smoking to an aerosoldevice, and wherein the determining method and product variables of atransition regimen for transitioning the smoker from cigarette smokingto an aerosol device comprises: determining, by predictive learning,method and product variables of a transition regimen for transitioningthe smoker from cigarette smoking to an aerosol device based on weighingthe method and product variables of transition regimens fortransitioning the smokers from cigarette smoking to the tobacco anaerosol device according to probabilities that the method and productvariables of transition regimens for transitioning the smokers fromcigarette smoking to an aerosol device will transition the smoker fromcigarette smoking to an aerosol device.
 13. The system of claim 11,wherein each of the demographic of the respective smoker and thedemographic data of the smoker comprises at least one of age, race,gender, ethnicity, national origin, education level, occupation, andmarital status.
 14. The system of claim 13, wherein each of the tobaccouse characteristics of the smoker and the tobacco use characteristic ofthe respective smoker comprises at least one of number of years smoking,number of packs per day, Fagerstrom dependence score, pack-year rating,total smoke dependence score, average number of cigarettes smoked perday over the last month, usual cigarette brand, current or previous useof nicotine products including e-cigarettes, current or previous use ofa tobacco heating product, current or previous use of any other tobaccoproducts, number of previous cigarette quit attempts if any, and levelof interest in switching to e-cigarettes or a tobacco heating productcompared to level of interest in quitting tobacco altogether.
 15. Thesystem of claim 14, wherein the method and product variables of thetransition regimen the smoker from cigarette smoking to an aerosoldevice are selected from among the method and product variables oftransition regimens for transitioning smokers from cigarette smoking toan aerosol device of the one or more smoker profiles in the databasehaving demographic and tobacco use characteristics of the respectivesmokers similar to the demographic characteristics and tobacco usecharacteristics of the smoker.
 16. The system of claim 15, wherein thetransition regimen for transitioning the smoker from cigarette smokingto an aerosol device comprises a length of a transitional period, a typeof an aerosol device, a type of very low nicotine cigarettes, andrecommendations and instructions for using the type of an aerosol deviceand the type of the very low nicotine cigarettes during the transitionalperiod.
 17. A kit for transitioning a smoker of conventional cigarettesto using a tobacco heating device during a transitional period, said kitcomprising one or more compartments comprising very low nicotinecigarettes, a tobacco heating device, a supply of tobacco sticks andinformation and recommendations, wherein the transitional period is lessthan 85 days, wherein a number of very low nicotine cigarettes equals aproduct of an average number of cigarettes the smoker smokes per day anda number of days in the transitional period, multiplied by a factor ofat least 17 percent, wherein each of the very low nicotine cigarettescomprises equal to or less than 2.0 mg of nicotine, wherein a number oftobacco sticks equals at least a product of the average number ofcigarettes the smoker smokes per day over a time period and the numberof days in the transitional period, wherein each of the tobacco stickscomprises equal to or greater than 2.0 mg of nicotine, and wherein theinformation and recommendations include instructions on how the smokeruses the very low nicotine cigarettes and the tobacco heating deviceduring the transitional period in an attempt by the smoker to switchfrom smoking cigarettes to using a tobacco heating device.
 18. The kitof claim 17, wherein each of the very low nicotine cigarettes furthercomprises a collective cannabinoid content at least 1 mg.
 19. The kit ofclaim 18, wherein each of the very low nicotine cigarettes furthercomprises very low Δ9-tetrahydrocannabinol (THC) cannabis comprisingΔ9-tetrahydrocannabinolic acid/Δ9-tetrahydrocannabinol of equal to orless than 1.25 mg/g.
 20. A system for transitioning a smoker fromcigarette smoking to a tobacco heating device, the system comprising: amemory storing a database of smoker profiles respectively in associationwith method and product variables of transition regimens fortransitioning smokers from cigarette smoking to a tobacco heatingdevice, each smoker profile comprising demographic and tobacco usecharacteristics of the respective smokers; and a processor configured toexecute a program for a method of providing a recommended transitionregimen for transitioning a smoker from cigarette smoking to a tobaccoheating device, the method comprising: receiving demographic data of thesmoker and tobacco usage data of the smoker; determining demographiccharacteristics and tobacco use characteristics of the smoker; based onthe demographic data of the smoker and the tobacco usage data of thesmoker; determining one or more smoker profiles in the database havingdemographic and tobacco use characteristics of the respective smokerssimilar to the demographic characteristics and tobacco usecharacteristics of the smoker; determining method and product variablesof a transition regimen for transitioning the smoker from cigarettesmoking to a tobacco heating device based on the product variables oftransition regimens for transitioning the smokers from cigarette smokingto a tobacco heating device; and providing, to the smoker, thetransition regimen for transitioning the smoker from cigarette smokingto a tobacco heating device.
 21. The system of claim 20, wherein therespective smokers comprise smokers successfully transitioning fromcigarette smoking to the tobacco a tobacco heating device, smokerscurrently transitioning from cigarette smoking to a tobacco heatingdevice, and smokers unsuccessfully transitioning from cigarette smokingto a tobacco heating device, and wherein the determining method andproduct variables of a transition regimen for transitioning the smokerfrom cigarette smoking to a tobacco heating device comprises:determining, by predictive learning, method and product variables of atransition regimen for transitioning the smoker from cigarette smokingto a tobacco heating device based on weighing the method and productvariables of transition regimens for transitioning the smokers fromcigarette smoking to a tobacco heating device according to probabilitiesthat the method and product variables of transition regimens fortransitioning the smokers from cigarette smoking to a tobacco heatingdevice will transition the smoker from cigarette smoking to a tobaccoheating device.
 22. The system of claim 21, wherein each of thedemographic characteristics of the respective smokers and thedemographic data of the smoker comprises at least one of age, race,gender, ethnicity, national origin, education level, occupation, andmarital status.
 23. The system of claim 22, wherein each of the tobaccouse characteristics of the smoker and the tobacco use characteristic ofthe respective smokers comprise at least one of number of years smoking,number of packs per day, Fagerstrom dependence score, pack-year rating,total smoke dependence score, average number of cigarettes smoked perday over a time period, usual cigarette brand, current or previous useof nicotine products including e-cigarettes, current or previous use ofa tobacco heating product, current or previous use of any other tobaccoproducts, number of previous cigarette quit attempts if any, level ofinterest in switching to a tobacco heating product, and level ofinterest in quitting tobacco use altogether.
 24. The system of claim 23,wherein the method and product variables of the transition regimen areselected from among the method and product variables of transitionregimens for transitioning smokers from cigarette smoking to a tobaccoheating device of one or more smoker profiles in the database havingdemographic and tobacco use characteristics of the respective smokerssimilar to the demographic characteristics and tobacco usecharacteristics of the smoker.
 25. The system of claim 24, wherein thetransition regimen for transitioning the smoker from cigarette smokingto a tobacco heating device comprises a length of a transitional period,a type of a tobacco heating device, a type of very low nicotinecigarettes, and recommendations and instructions for using the type of atobacco heating device and the type of the very low nicotine cigarettesduring the transitional period.